Dysregulation of Wnt/β-catenin signaling has been associated with the development and progression of many cancers. The stability and subcellular localization of β-catenin, a dual functional protein that plays a role in intracellular adhesion and in regulating gene expression, is tightly regulated. However, little is known about the transcriptionally active form of β-catenin, Active Beta Catenin (ABC), that is unphosphorylated at serine 37 (Ser37) and threonine 41 (Thr41). Elucidating the mechanism by which β-catenin is activated to generate ABC is vital to the development of therapeutic strategies to block β-catenin signaling for cancer treatment. Using melanoma, breast and prostate cancer cell lines, we show that while cellular β-catenin levels are regulated by the Wnt pathway, cellular ABC levels are mainly regulated by the PI3K pathway and are dependent on the phosphatase activity of the protein phosphatase PP2A. Furthermore, we demonstrate that although the PI3K/PTEN pathway does not regulate total β-catenin protein levels within the cell, it plays a role in regulating the subcellular localization of β-catenin. Our results support a novel functional interaction/cross-talk between the PTEN/PI3K and Wnt pathways in the regulation of the subcellular/nuclear levels of ABC, which is crucially important for the protein's activity as a transcription factor and its biological effects in health and disease.

Background: The care of rural trauma patients in northern Alberta can be extremely challenging because of the vast geographic area, the limited access to health care facilities and the lack of adequate resources to manage severe injuries. Identifying gaps in equipment and personnel in rural centres can provide opportunities for improving the care of injured patients in these environments. We conducted a survey based on Canadian Accreditation Council quality indicators to evaluate trauma infrastructure and human resources in rural centres across northern Alberta. Methods: A standardized survey was developed to assess the availability of trauma-specific equipment and personnel across the prehospital and emergency department (ED) settings. The survey was distributed to 50 peripheral hospitals biannually from January 2017 to September 2018. Two-tailed paired t tests were used to evaluate changes in survey responses; a p value of less than 0.05 was considered statistically significant. Results: The survey response rate was 100%. By the end of the study period, there were significant improvements in the number of providers (p = 0.04), nurses (p = 0.01) and dedicated trauma resuscitation bays (p = 0.04) in the ED for managing injured patients. There were also significant increases in the availability of equipment, including advanced airway management tools (p = 0.02), rapid infusion devices (p = 0.02) and warmers (p = 0.04). Access to x-ray equipment (p = 0.03) and computed tomography (CT) scanners (p = 0.04) as well as equipment to support telehealth and teleconferencing (p = 0.04) increased during the study period. Access to, and supply of, blood products also increased significantly (p = 0.02) during the study period. Conclusion: Our study demonstrates that the trauma resources of rural health care centres may be evaluated in a standardized fashion centres, and the results point to opportunities to remedy gaps in equipment and personnel. Our methods may be applied to any trauma network that serves geographically large areas with a sparse distribution of health care facilities, to provide critical information for the optimization of resources in rural trauma. Contexte : Les soins aux patients victimes de traumatismes en région rurale dans le nord de l'Alberta peuvent être très difficiles en raison de la superficie de la région, de l'accès limité aux établissements de santé et du manque de ressources pour soigner adéquatement les blessures graves. En repérant les lacunes en équipement et en personnel dans les établissements en région rurale, on peut créer des occasions d'améliorer les soins aux patients blessés dans ces milieux. Nous avons mené un sondage fondé sur les indicateurs de qualité du Conseil d'accréditation canadien pour évaluer les infrastructures et les ressources humaines en traumatologie dans les établissements des régions rurales du nord de l'Alberta. Méthodes : Un sondage standardisé a été créé pour évaluer la disponibilité des équipements et des ressources humaines en traumatologie en contexte préhosp...

Background Perinatal brain injury results in neurodevelopmental disabilities (neuroDDs) that include cerebral palsy, autism, attention deficit disorder, epilepsy, learning disabilities and others. Commonly, injury occurs when placental circulation, that is responsible for transporting nutrients and oxygen to the fetus, is compromised. Placental insufficiency (PI) is a reduced supply of blood and oxygen to the fetus and results in a hypoxic-ischemic (HI) environment. A significant HI state in-utero leads to perinatal compromise, characterized by fetal growth restriction and brain injury. Given that over 80% of perinatal brain injuries that result in neuroDDs occur during gestation, prior to birth, preventive approaches are needed to reduce or eliminate the potential for injury and subsequent neuroDDs. Sulforaphane (SFA) derived from cruciferous vegetables such as broccoli sprouts (BrSps) is a phase-II enzyme inducer that acts via cytoplasmic Nrf2 to enhance the production of anti-oxidants in the brain through the glutathione pathway. We have previously shown a profound in vivo neuro-protective effect of BrSps/SFA as a dietary supplement in pregnant rat models of both PI and fetal inflammation. Strong evidence also points to a role for SFA as treatment for various cancers. Paradoxically, then SFA has the ability to enhance cell survival, and with conditions of cancer, enhance cell death. Given our findings of the benefit of SFA/Broccoli Sprouts as a dietary supplement during pregnancy, with improvement to the fetus, it is important to determine the beneficial and toxic dosing range of SFA. We therefore explored, in vitro, the dosing range of SFA for neuronal and glial protection and toxicity in normal and oxygen/glucose deprived (OGD) cell cultures. Methods OGD simulates, in vitro, the condition experienced by the fetal brain due to PI. We developed a cell culture model of primary cortical neuronal, astrocyte and combined brain cell co-cultures from newborn rodent brains. The cultures were exposed to an OGD environment for various durations of time to determine the LD50 (duration of OGD required for 50% cell death). Using the LD50 as the time point, we evaluated the efficacy of varying doses of SFA for neuroprotective and neurotoxicity effects. Control cultures were exposed to normal media without OGD, and cytotoxicity of varying doses of SFA was also evaluated. Immunofluorescence (IF) and Western blot analysis of cell specific markers were used for culture characterization, and quantification of LD50. Efficacy and toxicity effect of SFA was assessed by IF/high content microscopy and by AlamarBlue viability assay, respectively. Results We determined the LD50 to be 2 hours for neurons, 8 hours for astrocytes, and 10 hours for co-cultures. The protective effect of SFA was noticeable at 2.5 μM and 5 μM for neurons, although it was not significant. There was a significant protective effect of SFA at 2.5 μM (p<0.05) for astrocytes and co-cultures. Significant toxicity ranges were also confirmed in OGD cultures as ≥ 100 μM (p<0.05) for astrocytes, ≥ 50 μM (p<0.01) for co-cultures, but not toxic in neurons; and toxic in control cultures as ≥ 100 μM (p<0.01) for neurons, and ≥ 50 μM (p<0.01) for astrocytes and co-cultures. One Way ANOVA and Dunnett’s Multiple Comparison Test were used for statistical analysis. Conclusions Our results indicate that cell death shows a trend to reduction in neuronal and astrocyte cultures, and is significantly reduced in co-cultures treated with low doses of SFA exposed to OGD. Doses of SFA that were 10 times higher were toxic, not only under conditions of OGD, but in normal control cultures as well. The findings suggest that: 1. SFA shows promise as a preventative agent for fetal ischemic brain injury, and 2. Because the fetus is a rapidly growing organism with profound cell multiplication, dosing parameters must be established to insure safety within efficacious ranges. This study will influence the development of innovative therapies for the prevention of childhood neuroDD.

Background The incidence of depression, anxiety, and post-traumatic stress disorders is reported to be as high as 50% in trauma patients. The perpetual negative emotions and state of mind in these disorders predisposes patients to negative mental health outcomes. Mindfulness, on the other hand, helps people to process their experience and emotions in a non-judgmental manner, and recently, there has been increased utilization of mindfulness-based therapies for the treatment of mental health conditions. This proof-of-concept study evaluates the use of a mindfulness-based online application in patients admitted to the trauma service at a Level 1 Trauma Centre. Methods Trauma patients who were English speaking, over the age of 18, and without brain injury or pre-existing neurocognitive disorder were included. Participants completed the Depression Anxiety Stress Scale (DASS)-21 to assess level of depression, anxiety, and stress, and the Connor-Davidson Resilience Scale (CD-RISC) to assess level of resiliency. Then, after 28 consecutive days of practicing mindfulness using the app ‘Stop, Breathe, and Think,’ the questionnaires were repeated and an exit survey conducted. Results For this study, 13 participants were enrolled, 2 withdrew, and 5 were lost to follow-up. The mean DASS-21 score at time enrollment was 16.4 and was 11.2 at follow-up ( p = 0.10). There were no differences between the level of depression and stress from enrollment to follow-up, but there was significant decrease in anxiety symptoms from 7.2 to 3.0 (<0.05). CD-RISC scores at enrollment and follow-up were 77.8 and 81 ( p = 0.23), respectively. At the time of exit interview, 67% of patients continued to use the application three to four times a week and 67% responded they plan to continue using the application. In addition, 83% of patients always or often felt better after practicing mindfulness and stated they would recommend the application to others. Conclusions Mindfulness shows promising potential to decrease psychological distress in trauma patients.