Inhibition of the MEK1/ERK pathway reduces arachidonic acid release independently of cPLA(2) phosphorylation and translocation

BACKGROUND: The 85-kDa cytosolic phospholipase A(2) (cPLA(2)) mediates arachidonic acid (AA) release in MDCK cells. Although calcium and mitogen-activated protein kinases regulate cPLA(2), the correlation of cPLA(2) translocation and phosphorylation with MAPK activation and AA release is unclear. RESULTS: MEK1 inhibition by U0126 inhibited AA release in response to ATP and ionomycin. This directly correlated with inhibition of ERK activation but not with phosphorylation of cPLA(2) on Ser(505), which was only partially inhibited by ERK inhibition. Inhibition of AA release by U0126 was still observed when stoichiometric phosphorylation of cPLA(2) on Ser(505) was maintained by activating p38 with anisomycin. Translocation kinetics of wild-type cPLA(2) and cPLA(2) containing S505A or S727A mutations to Golgi were similar in response to ATP and ionomycin and were not affected by U0126. CONCLUSIONS: These results suggest that the ability of cPLA(2) to hydrolyze membrane phospholipid is reduced by inhibition of the MEK1/ERK pathway and that the reduction in activity is independent of cPLA(2) phosphorylation and translocation to membrane. The results also demonstrate that cPLA(2) mutated at the phosphorylation sites Ser(505) and Ser(727) translocated with similar kinetic as wild-type cPLA(2)

Novel penalised likelihood reconstruction of PET in the assessment of histologically verified small pulmonary nodules

OBJECTIVES: Investigate the effect of a novel Bayesian penalised likelihood (BPL) reconstruction algorithm on analysis of pulmonary nodules examined with 18F-FDG PET/CT, and to determine its effect on small, sub-10-mm nodules. METHODS: 18F-FDG PET/CTs performed for nodule evaluation in 104 patients (121 nodules) were retrospectively reconstructed using the new algorithm, and compared to time-of-flight ordered subset expectation maximisation (OSEM) reconstruction. Nodule and background parameters were analysed semi-quantitatively and visually. RESULTS: BPL compared to OSEM resulted in statistically significant increases in nodule SUV(max) (mean 5.3 to 8.1, p < 0.00001), signal-to-background (mean 3.6 to 5.3, p < 0.00001) and signal-to-noise (mean 24 to 41, p < 0.00001). Mean percentage increase in SUV(max) (%ΔSUV(max)) was significantly higher in nodules ≤10 mm (n = 31, mean 73 %) compared to >10 mm (n = 90, mean 42 %) (p = 0.025). Increase in signal-to-noise was higher in nodules ≤10 mm (224 %, mean 12 to 27) compared to >10 mm (165 %, mean 28 to 46). When applying optimum SUV(max) thresholds for detecting malignancy, the sensitivity and accuracy increased using BPL, with the greatest improvements in nodules ≤10 mm. CONCLUSION: BPL results in a significant increase in signal-to-background and signal-to-noise compared to OSEM. When semi-quantitative analyses to diagnose malignancy are applied, higher SUV(max) thresholds may be warranted owing to the SUV(max) increase compared to OSEM. KEY POINTS: • Novel Bayesian penalised likelihood PET reconstruction was applied for lung nodule evaluation. • This was compared to current standard of care OSEM reconstruction. • The novel reconstruction generated significant increases in lung nodule signal-to-background and signal-to-noise. • These increases were highest in small, sub-10-mm pulmonary nodules. • Higher SUV(max)thresholds may be warranted when using semi-quantitative analyses to diagnose malignancy

The effect of habitual and experimental antiperspirant and deodorant product use on the armpit microbiome

An ever expanding body of research investigates the human microbiome in general and the skin microbiome in particular. Microbiomes vary greatly from individual to individual. Understanding the factors that account for this variation, however, has proven challenging, with many studies able to account statistically for just a small proportion of the inter-individual variation in the abundance, species richness or composition of bacteria. The human armpit has long been noted to host a high biomass bacterial community, and recent studies have highlighted substantial inter-individual variation in armpit bacteria, even relative to variation among individuals for other body habitats. One obvious potential explanation for this variation has to do with the use of personal hygiene products, particularly deodorants and antiperspirants. Here we experimentally manipulate product use to examine the abundance, species richness, and composition of bacterial communities that recolonize the armpits of people with different product use habits. In doing so, we find that when deodorant and antiperspirant use were stopped, culturable bacterial density increased and approached that found on individuals who regularly do not use any product. In addition, when antiperspirants were subsequently applied, bacterial density dramatically declined. These culture-based results are in line with sequence-based comparisons of the effects of long-term product use on bacterial species richness and composition. Sequence-based analyses suggested that individuals who habitually use antiperspirant tended to have a greater richness of bacterial OTUs in their armpits than those who use deodorant. In addition, individuals who used antiperspirants or deodorants long-term, but who stopped using product for two or more days as part of this study, had armpit communities dominated by Staphylococcaceae, whereas those of individuals in our study who habitually used no products were dominated by Corynebacterium. Collectively these results suggest a strong effect of product use on the bacterial composition of armpits. Although stopping the use of deodorant and antiperspirant similarly favors presence of Staphylococcaceae over Corynebacterium, their differential modes of action exert strikingly different effects on the richness of other bacteria living in armpit communities

18F-FDG PET/CT assessment of histopathologically confirmed mediastinal lymph nodes in non-small cell lung cancer using a penalised likelihood reconstruction

Purpose To investigate whether using a Bayesian penalised likelihood reconstruction (BPL) improves signal-to-background (SBR), signal-to-noise (SNR) and SUVmax when evaluating mediastinal nodal disease in non-small cell lung cancer (NSCLC) compared to ordered subset expectation maximum (OSEM) reconstruction. Materials and methods 18F-FDG PET/CT scans for NSCLC staging in 47 patients (112 nodal stations with histopathological confirmation) were reconstructed using BPL and compared to OSEM. Node and multiple background SUV parameters were analysed semi-quantitatively and visually. Results Comparing BPL to OSEM, there were significant increases in SUVmax (mean 3.2–4.0, p<0.0001), SBR (mean 2.2–2.6, p<0.0001) and SNR (mean 27.7–40.9, p<0.0001). Mean background SNR on OSEM was 10.4 (range 7.6–14.0), increasing to 12.4 (range 8.2–16.7, p<0.0001). Changes in background SUVs were minimal (largest mean difference 0.17 for liver SUVmean, p<0.001). There was no significant difference between either algorithm on receiver operating characteristic analysis (p=0.26), although on visual analysis, there was an increase in sensitivity and small decrease in specificity and accuracy on BPL. Conclusion BPL increases SBR, SNR and SUVmax of mediastinal nodes in NSCLC compared to OSEM, but did not improve the accuracy for determining nodal involvement

Potential recruitment into a clinical trial of vascular secondary prevention medications in cerebral small vessel disease, based on concomitant medication use

This research has been conducted using the UK Biobank resource. The authors are grateful to UK Biobank participants. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation.Peer reviewedPublisher PD

L.I.E.S. of omission: complex observation processes in ecology

Advances in statistics mean that it is now possible to tackle increasingly sophisticated observation processes. The intricacies and ambitious scale of modern data collection techniques mean that this is now essential. Methodological research to make inference about the biological process while accounting for the observation process has expanded dramatically, but solutions are often presented in field-specific terms, limiting our ability to identify commonalities between methods. We suggest a typology of observation processes that could improve translation between fields and aid methodological synthesis. We propose the LIES framework (defining observation processes in terms of issues of Latency, Identifiability, Effort and Scale) and illustrate its use with both simple examples and more complex case studies

Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease:a propensity-score matched cohort study

BackgroundBisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects.ObjectivesThe aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time.DesignThis was a new-user cohort study design with propensity score matching.Setting and data sourcesData were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1–3 and from the Danish Odense University Hospital Databases for work package 4.ParticipantsPatients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of &lt; 45 ml/minute/1.73 m2 were eligible. A second estimated glomerular filtration rate value of &lt; 45 ml/minute/1.73 m2 within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1–3. Patients with &lt; 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1–4.Interventions/exposureBisphosphonate use, identified from primary care prescriptions (for work packages 1–3) or pharmacy dispensations (for work package 4), was the main exposure.Main outcome measuresWork package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change.ResultsBisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users.LimitationsConfounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively.ConclusionsBisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness.Future workRandomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data

Rapid Generation of Kilonova Light Curves Using Conditional Variational Autoencoder

The discovery of the optical counterpart, along with the gravitational waves from GW170817, of the first binary neutron star merger, opened up a new era for multi-messenger astrophysics. Combining the GW data with the optical counterpart, also known as AT2017gfo, classified as a kilonova, has revealed the nature of compact binary merging systems by extracting enriched information about the total binary mass, the mass ratio, the system geometry, and the equation of state. Even though the detection of kilonova brought about a revolution in the domain of multi-messenger astronomy, since there has been only one kilonova from a gravitational wave detected binary neutron star merger event so far, this limits the exact understanding of the origin and propagation of the kilonova. Here, we use a conditional variational autoencoder trained on light curve data from two kilonova models having different temporal lengths, and consequently, generate kilonova light curves rapidly based on physical parameters of our choice with good accuracy. Once trained, the time scale for light curve generation is of the order of a few milliseconds, thus speeding up generating light curves by $1000$ times compared to the simulation. The mean squared error between the generated and original light curves is typically $0.015$ with a maximum of $0.08$ for each set of considered physical parameter; while having a maximum of $\approx0.6$ error across the whole parameter space. Hence, implementing this technique provides fast and reliably accurate results.Comment: 19 pages, 7 figures (3 additional figures in appendix), accepted to Ap

Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin

Additional file 4: Figure S3. Integrated genomic viewer (IGV) of BRCA2 gene. IGV displays genomic data of the PA-018 PAAC PDTX model. Chromosome 13 (Chr 13) is shown and 5bp deletions are found after position 32907365 (c.1755_1759del5), this region resides on exon 10 of BRCA2. The bottom of the image shows the nucleotides and amino acids that correspond to the reference sequence of the BRCA2 gene and protein