Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine.

Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. Tumor cells were then treated with combinations of nifurtimox and BSO and evaluated for viability using MTT assays. All neural tumor cell lines were sensitive to nifurtimox, and IC50 values ranged from approximately 20 to 210 μM. Nifurtimox treatment inhibited ERK phosphorylation and induced apoptosis in tumor cells. Furthermore, the combination of nifurtimox and BSO demonstrated significant synergistic efficacy in all tested cell lines. Additional preclinical and clinical studies of the combination of nifurtimox and BSO in patients with neural tumors are warranted

Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression.

BackgroundNovel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models.MethodsLevels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes.ResultsBoth primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib.ConclusionsNeuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify patients that may respond to MEK inhibition. MEK inhibition therefore represents a potential new therapeutic strategy for neuroblastoma

Global MHD simulation of flux transfer events at the high-latitude magnetopause observed by the cluster spacecraft and the SuperDARN radar system

A global magnetohydrodynamic numerical simulation is used to study the large-scale structure and formation location of flux transfer events (FTEs) in synergy with in situ spacecraft and ground-based observations. During the main period of interest on the 14 February 2001 from 0930 to 1100 UT the Cluster spacecraft were approaching the Northern Hemisphere high-latitude magnetopause in the postnoon sector on an outbound trajectory. Throughout this period the magnetic field, electron, and ion sensors on board Cluster observed characteristic signatures of FTEs. A few minutes delayed to these observations the Super Dual Auroral Radar Network (SuperDARN) system indicated flow disturbances in the conjugate ionospheres. These “two-point” observations on the ground and in space were closely correlated and were caused by ongoing unsteady reconnection in the vicinity of the spacecraft. The three-dimensional structures and dynamics of the observed FTEs and the associated reconnection sites are studied by using the Block-Adaptive-Tree-Solarwind-Roe-Upwind-Scheme (BATS-R-US) MHD code in combination with a simple open flux tube motion model (Cooling). Using these two models the spatial and temporal evolution of the FTEs is estimated. The models fill the gaps left by measurements and allow a “point-to-point” mapping between the instruments in order to investigate the global structure of the phenomenon. The modeled results presented are in good correlation with previous theoretical and observational studies addressing individual features of FTEs

Introduction and Validation of the Juror Decision Scale (JDS): An Empirical Investigation of the Story Model

Purpose: To develop and validate a self-report measure of individual juror decision making within criminal trials, based on theoretical features set out in the Story Model of juror decision making. Methods: The Juror Decision Scale (JDS) and Acceptance of Modern Myths about Sexual Aggression (AMMSA) measure were completed by 324 jury-eligible participants split across 27 jury panels, after observing a rape trial re-enactment high in ecological validity. Dimensionality and construct validity of the JDS was investigated using traditional confirmatory factor analysis (CFA) techniques alongside confirmatory bifactor analysis at two time points (individual juror verdict decisions pre- and post-deliberation). Three competing models of the JDS were specified and tested using Mplus with maximum likelihood robust estimation. Results: Bifactor model with three meaningful factors (complainant believability, defendant believability, decision confidence) was the best fit for the data at both decision points. Good composite reliability and differential predictive validity were observed for the three JDS subscales. Conclusion: Alongside demonstrating its multidimensional conceptualisation, the JDS development permits future empirical testing of the Story Model theoretical assertions surrounding juror decision making. Present findings also provide early evidence of a certainty principle assessment process governing individual verdict decision formation. Theoretical and practical applications are discussed

Patient reporting of complications after surgery: What impact does documenting postoperative problems from the perspective of the patient using telephone interview and postal questionnaires have on the identification of complications after surgery?

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Objectives To identify the frequency of postoperative complications, including problems identified by patients and complications occurring after discharge from hospital. To identify how these impact on quality of life (QoL) and the patient's perception of the success of their treatment. Design Data from three prospective sources: Surgical audit, a telephone interview (2 weeks after discharge) and a patient-focused questionnaire (2 months after surgery) were retrospectively analysed. Setting Dunedin Hospital, Dunedin, New Zealand. Participants Of the 500 patients, 100 undergoing each of the following types of surgeries: Anorectal, biliary, colorectal, hernia and skin. Primary and secondary outcome measures The primary outcomes were complications and the 36-item Short Form Health Survey (SF-36). Secondary outcomes included the patient's ratings of their treatment and a questionnaire-derived patient satisfaction score. Results 226 patients reported a complication; there were 344 separate complications and 411 reports of complications (16% of complications were reported on more than one occasion). The audit, telephone interview and questionnaire captured 12.6%, 36.3% and 51% of the 411 reports, respectively. Patients with complications had a lower SF-36 Physical Composite Summary (PCS) score (48.5 vs 43.9, p=0.021) and a lower Patient Satisfaction Score (85.6 vs 74.6, p<0.001). Rating of information received, care received, symptoms experienced, QoL and satisfaction with surgery were all significantly worse for patients with complications. On linear regression analysis, surgical complications, American Society of Anaesthesiologists score and age all made a similar contribution to the SF-36 PCS score, with standardised beta coefficients between 0.19 and 0.21. Conclusions Following surgery, over 40% of patients experienced complications. The QoL and satisfaction score were significantly less than for those without complications. The majority of complications were diagnosed after discharge from hospital. Taking more notice of the patient perspective helps us to identify problems, to understand what is important to them and may suggest ways to improve perioperative care

Facets of Psychopathy in Relation to Trauma-Exposure and Posttraumatic Stress Symptomology in a Sample of Incarcerated Male Offenders

Purpose: The aim was to investigate the moderating role of psychopathy facets on the relationship between traumatic exposure and posttraumatic stress disorder (PTSD) symptomology. Design/methodology/approach: Participants were male prisoners incarcerated in the U.K. Findings: The analysis revealed differential associations between the two facets of psychopathy, with potentially traumatic events and symptoms of PTSD. Specifically, neither primary psychopathy nor trauma exposure were significantly related to PTSD, while secondary psychopathy was positively and significantly related with PTSD symptoms. Furthermore, the effect of trauma exposure on PTSD was found to depend on the level of secondary psychopathy. More specifically, trauma exposure was strongly and positively associated with PTSD symptoms for low levels of secondary psychopathy and negatively associated with PTSD symptomology for individuals with high levels of secondary psychopathy. Originality/value: The findings clarify linkages among psychopathy facets, trauma, and PTSD, and extend our understanding of the presentation of PTSD in male prisoners

GGE Biplot Analysis of Forage Yield Performance and Stability Assessment of Tall Fescue Experimental Populations Selected Under Grazing Pressure in a Stress Environment

Integrating the yield and stability of genotypes selected under grazing pressure is an important objective in breeding forage crops. Genotype × environment (G x E) interaction is a major source of inconsistency in crop performance across locations. As a result, a genotype is considered stable if it has a low contribution to the G x E interaction. This study explores the effects of G x E interaction on yield and stability of 10 tall fescue experimental populations selected for persistence under grazing pressure outside the area of adaptation of the species (stress environment). Six standard checks were included. The populations were tested in a randomized complete block design with 5 replications in 9 environments. The pooled analysis of variance (ANOVA) revealed highly significant (p \u3c 0.01) variations between populations, locations, years, and G × E interaction. The first two principal components generated by the GGE biplot accounted for 46.78% and 28.45% variation in GGE for yield. The locations (Athens and Blairsville) were found to be the most significant causes of yield variation. The GGE biplot revealed three winning populations GALA1301 (ga1), GALA1302 (ga2), and GALA1306 (ga6) in terms of yield across environments. These populations performed better than all the checks. GALA1502T (g2t) was the most stable and GALA1502A(g2a), GALA1301(ga1), and GALA1303(ga3) are both comparatively stable and high yield performers. Comparison of the two populations g2t and g2a that were selected from the same base population but in different environments (g2t selected for persistence at Tifton under grazing pressure and g2a selected for yield without grazing in Athens) showed that g2t was the most stable across environments but lower in yield than g2a. Our results suggest that selection under grazing pressure in stress environments could result in improved stability across environments while yield performance will still depend on the genetic background of the germplasm

Breeding Cool-Season Forage Grasses for a Warming Climate

In many parts of the world, changing climatic conditions are resulting in increased temperatures and more variable precipitation, intensifying the duration and severity of drought, especially in summer. Warming climate is considered one reason for the increasing failure of traditional, summer-active cool-season perennial grasses at the margin of their zone of adaptation in naturally C4 grass-dominated ecosystems of the Southern Great Plains of the USA. Two cool-season perennial forage grasses orchardgrass (Dactylis glomerata L.) and tall fescue (Lolium arundinaceum (Schreb.) Darbysh.) are of major economic and ecological importance in these regions. In 2008, we initiated a breeding program of summer-dormant (Mediterranean) cool-season perennial grasses originating from the Mediterranean Basin, including tall fescue, orchardgrass, and perennial ryegrass. In this publication, we present breeding history and morphological characteristics of cv. Yonatan (also known under research name TAL-02), a new cultivar of summer-dormant tall fescue. Recurrent selection cycles were conducted to develop cv. Yonatan during 2007-2010. Evaluations were performed on several locations across north Texas, Australia and New Zealand during 2015-2020. Yonatan tall fescue has improved forage production and persistence compared with check cultivars Flecha and Chisholm. It also differs from them in terms of wider leaves, earlier maturity, and development of a bulbous storage organ at the base of the tiller. Yonatan is adapted to changing climatic conditions in the Southern Great Plains of the USA, Australia, and New Zealand

Psychological distress and risk of myocardial infarction and stroke in the 45 and Up Study: a 1 prospective cohort study

Background The interplay between mental and physical health remains poorly understood. We investigated whether psychological distress is associated with risk of myocardial infarction (MI) and stroke in a population-based prospective study. Methods and Results We included participants without prior stroke/MI from the New South Wales 45 and Up Study. We categorized baseline psychological distress as low, medium, and high/very high on the 10-item Kessler Psychological Distress scale and identified stroke and MI through linkage to hospital admission and mortality records. We obtained sex and age-stratified adjusted and unadjusted hazard ratios for the association between psychological distress and MI and stroke. We investigated for interaction between psychological distress and each of age and sex. Among 221 677 participants, 16.2% and 7.3% had moderate and high/very high psychological distress at recruitment, respectively. During 4.7 (±0.98 SD) years of follow-up, 4573 MIs and 2421 strokes occurred. Absolute risk of MI and stroke increased with increasing psychological distress level. In men aged 45 to 79 years, high/very high versus low psychological distress was associated with a 30% increased risk of MI (fully adjusted hazard ratios, 1.30; 95% CI, 1.12-1.51), with weaker estimates in those aged ≥80 years. Among women, high/very high psychological distress was associated with an 18% increased risk of MI (adjusted hazard ratio, 1.18; 95% CI, 0.99-1.42) with similar findings across age groups. In the age group of participants aged 45 to 79 years, high/very high psychological distress and male sex had a supra-additive effect on MI risk. Similar estimates were observed for stroke, with high/very high psychological distress associated with a 24% and 44% increased stroke risk in men and women, respectively, with no evidence of interaction with age or sex. Conclusions Psychological distress has a strong, dose-dependent, positive association with MI and stroke in men and women, despite adjustment for a wide range of confounders