A comparison of analysis techniques for extracting resonance parameters from lattice Monte Carlo data

Different methods for extracting resonance parameters from Euclidean lattice field theory are tested. Monte Carlo simulations of the O(4) non-linear sigma model are used to generate energy spectra in a range of different volumes both below and above the inelastic threshold. The applicability of the analysis methods in the elastic region is compared. Problems which arise in the inelastic region are also emphasised.Comment: 17 pages, 20 figures; clarification and minor corrections added, to appear in PR

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance

Clinical response to primary letrozole therapy in elderly patients with early breast cancer : possible role for p53 as a biomarker

Primary tamoxifen therapy has been widely used to treat elderly women with ER-positive breast cancer in the past. Aromatase inhibitors may be more beneficial than tamoxifen when used as primary endocrine therapy in elderly patients. We aimed to retrospectively evaluate a series of elderly women with ER-positive breast cancer treated with primary letrozole therapy as sole therapy with a minimum of 5 years follow up. To identify possible predictive biomarkers a pilot immunohistochemical analysis was performed to assess the expression of PR, HER2, EGFR, BCL2 and p53. A total of 45 women, aged more than 70 years with a diagnosis of ER-positive breast cancer that was treated with primary letrozole therapy were identified. A case note review was undertaken to obtain clinical information. Formalin fixed paraffin embedded tumour tissue from diagnostic core biopsies was available for all patients. Immunohistochemical analysis was performed to establish the protein expression status of p53, PR, HER2, EGFR and BCL2. The mean age of the 45 patients was 87 years (range 70–101). Clinical benefit was seen in 60% of the patients. Median progression free survival was 53 months (95% CI – 34–72) and the median time to progression was 43 months (95% CI – 22–64). BCL2 was expressed in 45/45 (100%); PR in 38/45 (84%); EGFR in 13/45 (28%); HER2 in 9/45 (20%) and p53 in 5/45 (11%) of tissue samples. Positive expression of p53 was associated with poor progression free survival (p = 0.03) in this pilot study. This study demonstrates that letrozole as sole treatment appears to be a suitable treatment option for elderly patients with ER-positive breast cancer who are not fit for, or decline, surgery. The analysis of p53 in a larger study is warranted in order to assess its role as a biomarker in this patient group

Septic shock is correlated with asymmetrical dimethyl arginine levels, which may be influenced by a polymorphism in the dimethylarginine dimethylaminohydrolase II gene: a prospective observational study

INTRODUCTION: Asymmetrical dimethyl arginine (ADMA) is an endogenous non-selective inhibitor of nitric oxide synthase that may influence the severity of organ failure and the occurrence of shock secondary to an infectious insult. Levels may be genetically determined by a promoter polymorphism in a regulatory gene encoding dimethylarginine dimethylaminohydrolase II (DDAH II), which functions by metabolising ADMA to citrulline. The aim of this study was to examine the association between ADMA levels and the severity of organ failure and shock in severe sepsis and also to assess the influence of a promoter polymorphism in DDAH II on ADMA levels. METHODS: A prospective observational study was designed, and 47 intensive care unit (ICU) patients with severe sepsis and 10 healthy controls were enrolled. Serum ADMA and IL-6 were assayed on admission to the ICU and seven days later. Allelic variation for a polymorphism at position -449 in the DDAH II gene was assessed in each patient. Clinical and demographic details were also collected. RESULTS: On day 1 more ADMA was detectable in the ICU group than in the control group (p = 0.005). Levels subsequently increased during the first week in ICU (p = 0.001). ADMA levels were associated with vasopressor requirements on day one (p = 0.001). ADMA levels and Sequential Organ Failure Assessment scores were directly associated on day one (p = 0.0001) and day seven (p = 0.002). The degree of acidaemia and lactaemia was directly correlated with ADMA levels at both time points (p < 0.01). On day seven, IL-6 was directly correlated with ADMA levels (p = 0.006). The variant allele with G at position -449 in the DDAH II gene was associated with increased ADMA concentrations at both time points (p < 0.05). CONCLUSION: Severity of organ failure, inflammation and presence of early shock in severe sepsis are associated with increased ADMA levels. ADMA concentrations may be influenced by a polymorphism in the DDAH II gene

Determination of beam quality correction factors for the Roos plane-parallel ionisation chamber exposed to very high energy electron (VHEE) beams using Geant4

Detailed characterisation of the Roos secondary standard plane-parallel ionisation chamber has been conducted in a novel 200 MeV Very High Energy Electron (VHEE) beam with reference to the standard 12 MeV electron calibration beam used in our experimental work. Stopping-power-ratios and perturbation factors have been determined for both beams and used to calculated the beam quality correction factor using the Geant4 general purpose MC code. These factors have been calculated for a variety of charged particle transport parameters available in Geant4 which were found to pass the Fano cavity test. Stopping-power-ratios for the 12 MeV electron calibration beam quality were found to agree within uncertainties to that quoted by current dosimetry protocols. Perturbation factors were found to vary by up-to 4% for the calibration beam depending on the parameter configuration, compared with only 0.8% for the VHEE beam. Beam quality correction factors were found to describe an approximately 10% lower dose than would be originally calculated if a beam quality correction were not accounted for. Moreover, results presented here largely resolve unphysical chamber measurements, such as collection efficiencies greater than 100%, and assist in the accurate determination of absorbed dose and ion recombination in secondary standard ionisation chambers

Grazing of dairy cows on pasture versus indoor feeding on total mixed ration: Effects on low-moisture part-skim Mozzarella cheese yield and quality characteristics in mid and late lactation

peer-reviewedThis study investigated the effects of 3 dairy cow feeding systems on the composition, yield, and biochemical and physical properties of low-moisture part-skim Mozzarella cheese in mid (ML; May–June) and late (LL; October–November) lactation. Sixty spring-calving cows were assigned to 3 herds, each consisting of 20 cows, and balanced on parity, calving date, and pre-experimental milk yield and milk solids yield. Each herd was allocated to 1 of the following feeding systems: grazing on perennial ryegrass (Lolium perenne L.) pasture (GRO), grazing on perennial ryegrass and white clover (Trifolium repens L.) pasture (GRC), or housed indoors and offered total mixed ration (TMR). Mozzarella cheese was manufactured on 3 separate occasions in ML and 4 in LL in 2016. Feeding system had significant effects on milk composition, cheese yield, the elemental composition of cheese, cheese color (green to red and blue to yellow color coordinates), the extent of flow on heating, and the fluidity of the melted cheese. Compared with TMR milk, GRO and GRC milks had higher concentrations of protein and casein and lower concentrations of I, Cu, and Se, higher cheese-yielding capacity, and produced cheese with lower concentrations of the trace elements I, Cu, and Se and higher yellowness value. Cheese from GRO milk had higher heat-induced flow and fluidity than cheese from TMR milk. These effects were observed over the entire lactation period (ML + LL), but varied somewhat in ML and LL. Feeding system had little, or no, effect on gross composition of the cheese, the proportions of milk protein or fat lost to cheese whey, the texture of the unheated cheese, or the energy required to extend the molten cheese. The differences in color and melt characteristics of cheeses obtained from milks with the different feeding systems may provide a basis for creating points of differentiation suited to different markets.This study was funded by the Department of Agriculture, Food and the Marine (Dublin, Ireland) Stimulus fund (11/sf/309), and additionally supported by funding from the Dairy Levy Trust Co-Operative Society Limited (Dublin, Ireland)

The Transcriptional Regulator CBP Has Defined Spatial Associations within Interphase Nuclei

It is becoming increasingly clear that nuclear macromolecules and macromolecular complexes are compartmentalized through binding interactions into an apparent three-dimensionally ordered structure. This ordering, however, does not appear to be deterministic to the extent that chromatin and nonchromatin structures maintain a strict 3-D arrangement. Rather, spatial ordering within the cell nucleus appears to conform to stochastic rather than deterministic spatial relationships. The stochastic nature of organization becomes particularly problematic when any attempt is made to describe the spatial relationship between proteins involved in the regulation of the genome. The CREB–binding protein (CBP) is one such transcriptional regulator that, when visualised by confocal microscopy, reveals a highly punctate staining pattern comprising several hundred individual foci distributed within the nuclear volume. Markers for euchromatic sequences have similar patterns. Surprisingly, in most cases, the predicted one-to-one relationship between transcription factor and chromatin sequence is not observed. Consequently, to understand whether spatial relationships that are not coincident are nonrandom and potentially biologically important, it is necessary to develop statistical approaches. In this study, we report on the development of such an approach and apply it to understanding the role of CBP in mediating chromatin modification and transcriptional regulation. We have used nearest-neighbor distance measurements and probability analyses to study the spatial relationship between CBP and other nuclear subcompartments enriched in transcription factors, chromatin, and splicing factors. Our results demonstrate that CBP has an order of spatial association with other nuclear subcompartments. We observe closer associations between CBP and RNA polymerase II–enriched foci and SC35 speckles than nascent RNA or specific acetylated histones. Furthermore, we find that CBP has a significantly higher probability of being close to its known in vivo substrate histone H4 lysine 5 compared with the closely related H4 lysine 12. This study demonstrates that complex relationships not described by colocalization exist in the interphase nucleus and can be characterized and quantified. The subnuclear distribution of CBP is difficult to reconcile with a model where chromatin organization is the sole determinant of the nuclear organization of proteins that regulate transcription but is consistent with a close link between spatial associations and nuclear functions

A pre-post test evaluation of the impact of the PELICAN MDT-TME development programme on the working lives of colorectal cancer team members

Background - The PELICAN Multidisciplinary Team Total Mesorectal Excision (MDT-TME) Development Programme aimed to improve clinical outcomes for rectal cancer by educating colorectal cancer teams in precision surgery and related aspects of multidisciplinary care. The Programme reached almost all colorectal cancer teams across England. We took the opportunity to assess the impact of participating in this novel team-based Development Programme on the working lives of colorectal cancer team members. Methods - The impact of participating in the programme on team members' self-reported job stress, job satisfaction and team performance was assessed in a pre-post course study. 333/568 (59%) team members, from the 75 multidisciplinary teams who attended the final year of the Programme, completed questionnaires pre-course, and 6-8 weeks post-course. Results - Across all team members, the main sources of job satisfaction related to working in multidisciplinary teams; whilst feeling overloaded was the main source of job stress. Surgeons and clinical nurse specialists reported higher levels of job satisfaction than team members who do not provide direct patient care, whilst MDT coordinators reported the lowest levels of job satisfaction and job stress. Both job stress and satisfaction decreased after participating in the Programme for all team members. There was a small improvement in team performance. Conclusions - Participation in the Development Programme had a mixed impact on the working lives of team members in the immediate aftermath of attending. The decrease in team members' job stress may reflect the improved knowledge and skills conferred by the Programme. The decrease in job satisfaction may be the consequence of being unable to apply these skills immediately in clinical practice because of a lack of required infrastructure and/or equipment. In addition, whilst the Programme raised awareness of the challenges of teamworking, a greater focus on tackling these issues may have improved working lives further

Reducing prescribing errors through creatinine clearance alert redesign

Background Literature has shown that computerized creatinine clearance alerts reduce errors during prescribing, and applying human factors principles may further reduce errors. Our objective was to apply human factors principles to creatinine clearance alert design and assess whether the redesigned alerts increase usability and reduce prescribing errors compared with the original alerts. Methods Twenty Veterans Affairs (VA) outpatient providers (14 physicians, 2 nurse practitioners, and 4 clinical pharmacists) completed 2 usability sessions in a counterbalanced study to evaluate original and redesigned alerts. Each session consisted of fictional patient scenarios with 3 medications that warranted prescribing changes because of renal impairment, each associated with creatinine clearance alerts. Quantitative and qualitative data were collected to assess alert usability and the occurrence of prescribing errors. Results There were 43% fewer prescribing errors with the redesigned alerts compared with the original alerts (P = .001). Compared with the original alerts, redesigned alerts significantly reduced prescribing errors for allopurinol and ibuprofen (85% vs 40% and 65% vs 25%, P = .012 and P = .008, respectively), but not for spironolactone (85% vs 65%). Nine providers (45%) voiced confusion about why the alert was appearing when they encountered the original alert design. When laboratory links were presented on the redesigned alert, laboratory information was accessed 3.5 times more frequently. Conclusions Although prescribing errors were high with both alert designs, the redesigned alerts significantly improved prescribing outcomes. This investigation provides some of the first evidence on how alerts may be designed to support safer prescribing for patients with renal impairment