Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and A

Probing shock geometry via the charge to mass ratio dependence of heavy ion spectra from multiple spacecraft observations of the 2013 November 4 event

In large Solar Energetic Particle (SEP) events, ions can be accelerated at coronal mass ejection (CME)-driven shocks to very high energies. The spectra of heavy ions in many large SEP events show features such as roll-overs or spectral breaks. In some events when the spectra are plotted in terms of energy/nucleon, they can be shifted relative to each other to make the spectral breaks align. The amount of shift is charge to mass ratio (Q/A) dependent and varies from event to event. This can be understood if the spectra of heavy ions are organized by the diffusion coefficients (Cohen et al. 2005). In the work of Li et al. (2009), the Q/A dependence of the scaling is related to shock geometry when the CME-driven shock is close to the Sun. For events where multiple in-situ spacecraft observations exist, one may expect that different spacecraft are connected to different portions of the CME-driven shock that have different shock geometries, therefore yielding different Q/A dependence. In this work, we examine one SEP event which occurred on 2013 November 4. We study the Q/A dependence of the energy scaling for heavy ion spectra using helium, oxygen and iron ions. Observations from STEREO-A, STEREO-B and ACE are examined. We find that the scalings are different for different spacecraft. We suggest that this is because ACE, STEREO-A and STEREO-B are connected to different parts of the shock that have different shock geometries. Our analysis indicates that studying the Q/A scaling of in-situ particle spectra can serve as a powerful tool to remotely examine the shock geometry for large SEP events

Modelling Solar Energetic Neutral Atoms from Solar Flares and CME-driven Shocks

We examine the production of energetic neutral atoms (ENAs) in solar flares and CME-driven shocks and their subsequent propagation to 1 au. Time profiles and fluence spectra of solar ENAs at 1 au are computed for two scenarios: 1) ENAs are produced downstream at CME-driven shocks, and 2) ENAs are produced at large-scale post-flare loops in solar flares. Both the time profiles and fluence spectra for these two scenarios are vastly different. Our calculations indicate that we can use solar ENAs as a new probe to examine the underlying acceleration process of solar energetic particles (SEPs) and to differentiate the two accelertion sites: large loops in solar flares and downstream of CME-driven shocks, in large SEP events.Comment: 11 pages, updated figures and paper is accepted by Ap

An Electronic Clinical Decision Support System for the Management of Low Back Pain in Community Pharmacy: Development and Mixed Methods Feasibility Study

Background People with low back pain (LBP) in the community often do not receive evidence-based advice and management. Community pharmacists can play an important role in supporting people with LBP as pharmacists are easily accessible to provide first-line care. However, previous research suggests that pharmacists may not consistently deliver advice that is concordant with guideline recommendations and may demonstrate difficulty determining which patients require prompt medical review. A clinical decision support system (CDSS) may enhance first-line care of LBP, but none exists to support the community pharmacist–client consultation. Objective This study aimed to develop a CDSS to guide first-line care of LBP in the community pharmacy setting and to evaluate the pharmacist-reported usability and acceptance of the prototype system. Methods A cross-platform Web app for the Apple iPad was developed in conjunction with academic and clinical experts using an iterative user-centered design process during interface design, clinical reasoning, program development, and evaluation. The CDSS was evaluated via one-to-one user-testing with 5 community pharmacists (5 case vignettes each). Data were collected via video recording, screen capture, survey instrument (system usability scale), and direct observation. Results Pharmacists’ agreement with CDSS-generated self-care recommendations was 90% (18/20), with medicines recommendations was 100% (25/25), and with referral advice was 88% (22/25; total 70 recommendations). Pharmacists expressed uncertainty when screening for serious pathology in 40% (10/25) of cases. Pharmacists requested more direction from the CDSS in relation to automated prompts for user input and page navigation. Overall system usability was rated as excellent (mean score 92/100, SD 6.5; 90th percentile compared with similar systems), with acceptance rated as good to excellent. Conclusions A novel CDSS (high-fidelity prototype) to enhance pharmacist care of LBP was developed, underpinned by clinical practice guidelines and informed by a multidisciplinary team of experts. User-testing revealed a high level of usability and acceptance of the prototype system, with suggestions to improve interface prompts and information delivery. The small study sample limits the generalizability of the findings but offers important insights to inform the next stage of system development. </jats:sec

DNA methylation of the allergy regulatory gene interferon gamma varies by age, sex, and tissue type in asthmatics

Background Asthma is associated with allergic sensitization in about half of all cases, and asthma phenotypes can vary by age and sex. DNA methylation in the promoter of the allergy regulatory gene interferon gamma (IFNγ) has been linked to the maintenance of allergic immune function in human cell and mouse models. We hypothesized that IFNγ promoter methylation at two well-studied, key cytosine phosphate guanine (CpG) sites (-186 and -54), may differ by age, sex, and airway versus systemic tissue in a cohort of 74 allergic asthmatics. Results After sampling buccal cells, a surrogate for airway epithelial cells, and CD4+ lymphocytes, we found that CD4+ lymphocyte methylation was significantly higher in children compared to adults at both CpG sites (P <0.01). Buccal cell methylation was significantly higher in children at CpG -186 (P = 0.03) but not CpG -54 (P = 0.66). Methylation was higher in males compared to females at both CpG sites in CD4+ lymphocytes (-186: P <0.01, -54: P = 0.02) but not buccal cells (-186: P = 0.14, -54: P = 0.60). In addition, methylation was lower in CD4+ lymphocytes compared to buccal cells (P <0.01) and neighboring CpG sites were strongly correlated in CD4+ lymphocytes (r = 0.84, P <0.01) and weakly correlated in buccal cells (r = 0.24, P = 0.04). At CpG -186, there was significant correlation between CD4+ lymphocytes and buccal cells (r = 0.24, P = 0.04) but not at CpG -54 (r = -0.03, P = 0.78). Conclusions These findings highlight significant age, sex, and tissue-related differences in IFNγ promoter methylation that further our understanding of methylation in the allergic asthma pathway and in the application of biomarkers in clinical research

Association between preeclampsia and attention deficit hyperactivity disorder: a population-based and sibling-matched cohort study

Objective: Examine the association between preeclampsia and attention deficit hyperactivity disorder (ADHD), using a large Swedish‐based registry cohort. Methods: This study comprised 2,047,619 children, with 114,934 (5.6%) cases of ADHD. Preeclampsia was based on two alternate definitions: 1. Preeclampsia (using ICD‐9/ICD‐10) 2.Preeclampsia and small for gestational age (SGA) combined. ADHD was determined in one of two ways: 1. If a diagnosis of ADHD was present in the National Patient Register or 2.If an individual was in receipt of ADHD medication in the Prescribed Drug Register. Multivariate Cox proportional hazards regression analysis allowed adjustment for several perinatal/sociodemographic factors. Sibling‐matched analysis further controlled for shared genetic and familial confounding. Results: In the adjusted Cox model, preeclampsia was associated with an increase in likelihood of ADHD (HR: 1.15, 95% CI: 1.12, 1.19). The HR for preeclampsia and those born SGA was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, compared to those unexposed to preeclampsia/SGA. The sibling‐matched analysis did not materially change these associations (HR: 1.13, 95% CI: 1.05, 1.22) and 1.55 (95% CI: 1.28, 1.88). Conclusions: Exposure to preeclampsia or preeclampsia/SGA was associated with ADHD, independent of genetic/familial factors shared by siblings. However, it is important to note that sibling‐matched analysis can only adjust for factors that are constant between pregnancies, therefore residual confounding cannot be ruled out. Further research is needed to explore modifiable risk factors and identify those most‐at‐risk babies following delivery

Association between preeclampsia and autism spectrum disorder: a population-based study

Background: The environmental contribution of autism spectrum disorder (ASD) is approximately 17%–50%, highlighting the importance of investigating factors potentially contributing to the likelihood of its development, and of gaining a greater understanding of the pathogenesis surrounding ASD. The objective of this study was to examine the association between preeclampsia and ASD using a population‐based cohort study. Methods: All singleton live births in Sweden from 1982 to 2010 were included, using data from Swedish National Registers. Exposures of interest included: (a) preeclampsia (classified according to ICD‐8, ICD‐9 and ICD‐10) and (b) preeclampsia and small for gestational age (SGA) combined, used as a proxy for preeclampsia with placental dysfunction. ASD status was based on ICD‐9 and ICD‐10. The cohort consisted of 2,842,230 children, with 54,071 cases of ASD. Follow‐up began from the child's first birthday, and data were censored at first diagnosis of ASD, death, migration or end of study period (31st December 2016). We conducted multivariate Cox proportional hazards regression analysis, adjusting for several perinatal and sociodemographic factors, selected a priori. We further controlled for shared genetic and familial confounding using sibling‐matched analysis. Results: In the adjusted Cox proportional hazards regression analysis, preeclampsia was associated with a 25% increase in the likelihood of ASD (Hazard Ratio (HR): 1.25, 95% CI:1.19, 1.30) compared with those unexposed to preeclampsia, while in the sibling‐matched analysis the HR was 1.17 (95% CI: 1.06, 1.28). The HR for preeclampsia and SGA combined was 1.66 (95% CI: 1.49, 1.85) in the adjusted Cox model and 1.95 (95% CI: 1.53, 2.48) in the sibling‐matched analysis. Conclusions: Exposure to preeclampsia or preeclampsia/SGA (i.e. SGA baby exposed to preeclampsia) was associated with ASD. The stronger association with preeclampsia/SGA than preeclampsia alone suggests that placental pathology may be a mechanism for the increased likelihood of ASD

The association between preeclampsia and childhood development and behavioural outcomes

Objectives: To examine the associations between preeclampsia and longitudinal child developmental and behavioural outcomes using data from a nationally representative study of children living in Ireland. Methods: We used maternal-reported data from the Growing Up in Ireland longitudinal study of children. Data on preeclampsia and preeclampsia + small for gestational age (SGA) were collected when children were 9-months old. Data on child development and behavioural outcomes were collected at 9-months using the Ages and Stages Questionnaire (ASQ), and at 3 years, 5 years and 7–8 years using the Strengths and Difficulties Questionnaire (SDQ). Multivariate logistic regression analysis was used to examine the association between preeclampsia exposure and failure of ASQ domains, and abnormal SDQ domains. Linear spline multilevel models were used to examine the association between preeclampsia and preeclampsia + SGA and repeated measures of SDQ. All models controlled for several perinatal and sociodemographic factors. Results: A total of 10,692 children were included in the study at baseline, representing a weighted total of 70,791. Multivariate logistic regression suggested that preeclampsia was not associated with failing any ASQ domain. Preeclampsia was associated with abnormal SDQ cut-off of emotional (≥ 5) and hyperactivity (≥ 7) domains at age 5 years only. In the linear spline model, mean SDQ score was higher at each time point in exposed groups. Conclusions for Practice: While we did not find strong evidence of associations between preeclampsia and child developmental and behavioural outcomes overall, some associations between preeclampsia-exposure and subtle behavioural issues did persist. Further research is needed to replicate these findings, and determine the clinical significance of changes in SDQ scores