Although casein kinase 1δ (CK1δ) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/C(Cdh1)) ubiquitin ligase, and conditional deletion of the APC/C(Cdh1) activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/C(Cdh1) also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/C(Cdh1) controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.

Recent rapid growth in urban areas and the desire to create liveable neighbourhoods has brought about a renewed interest in planning for compact cities, with concepts like the 20-minute neighbourhood (20MN) becoming more popular. A 20MN broadly reflects a neighbourhood that allows residents to meet their daily (non-work) needs within a short, non-motorised, trip from home. The 20MN concept underpins the key planning strategy of Australia's second largest city, Melbourne, however the 20MN definition has not been operationalised. This study aimed to develop and operationalise a practical definition of the 20MN and apply this to two Australian state capital cities: Melbourne (Victoria) and Adelaide (South Australia).

Cardiovascular Disease (CVD) has been linked to "neighbourhood" socioeconomic status (nSES), often operationalized as a composite index of aggregate income, occupation and education within predefined administrative boundaries. The role of specific, non-composite socioeconomic markers has not been clearly explained. It is also unclear whether the relationship between nSES and CVD varies according to sex. We sought to determine whether area-level unemployment (ALU) was associated with CVD risk, and whether this association differed by sex.

Little is known about the situational contexts in which individuals consume processed sources of dietary sugars. This study aimed to describe the situational contexts associated with the consumption of sweetened food and drink products in a Catholic Middle Eastern Canadian community. A two-stage exploratory sequential mixed-method design was employed with a rationale of triangulation. In stage 1 (n = 62), items and themes describing the situational contexts of sweetened food and drink product consumption were identified from semi-structured interviews and were used to develop the content for the Situational Context Instrument for Sweetened Product Consumption (SCISPC). Face validity, readability and cultural relevance of the instrument were assessed. In stage 2 (n = 192), a cross-sectional study was conducted and exploratory factor analysis was used to examine the structure of themes that emerged from the qualitative analysis as a means of furthering construct validation. The SCISPC reliability and predictive validity on the daily consumption of sweetened products were also assessed. In stage 1, six themes and 40-items describing the situational contexts of sweetened product consumption emerged from the qualitative analysis and were used to construct the first draft of the SCISPC. In stage 2, factor analysis enabled the clarification and/or expansion of the instrument's initial thematic structure. The revised SCISPC has seven factors and 31 items describing the situational contexts of sweetened product consumption. Initial validation of the instrument indicated it has excellent internal consistency and adequate test-retest reliability. Two factors of the SCISPC had predictive validity for the daily consumption of total sugar from sweetened products (Snacking and Energy demands) while the other factors (Socialization, Indulgence, Constraints, Visual Stimuli and Emotional needs) were rather associated to occasional consumption of these products.

Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.

Kuwait is amongst countries in the Gulf region with high income economy. According to the World Health Organisation (WHO), one in five adults in the Gulf region is obese. This study sought to evaluate the prevalence and magnitude of association between overweight, obesity, central obesity, and socio-demographic factors in Kuwait.

Understanding how health outcomes are spatially distributed represents a first step in investigating the scale and nature of environmental influences on health and has important implications for statistical power and analytic efficiency. Using Australian and French cohort data, this study aimed to describe and compare the extent of geographic variation, and the implications for analytic efficiency, across geographic units, countries and a range of cardiometabolic parameters (Body Mass Index (BMI) waist circumference, blood pressure, resting heart rate, triglycerides, cholesterol, glucose, HbA1c). Geographic clustering was assessed using Intra-Class Correlation (ICC) coefficients in biomedical cohorts from Adelaide (Australia, n = 3893) and Paris (France, n = 6430) for eight geographic administrative units. The median ICC was 0.01 suggesting 1% of risk factor variance attributable to variation between geographic units. Clustering differed by cardiometabolic parameters, administrative units and countries and was greatest for BMI and resting heart rate in the French sample, HbA1c in the Australian sample, and for smaller geographic units. Analytic inefficiency due to clustering was greatest for geographic units in which participants were nested in fewer, larger geographic units. Differences observed in geographic clustering across risk factors have implications for choice of geographic unit in sampling and analysis, and highlight potential cross-country differences in the distribution, or role, of environmental features related to cardiometabolic health.

Self-selection into residential neighbourhoods is a widely acknowledged, but under-studied problem in research investigating neighbourhood influences on physical activity and diet. Failure to handle neighbourhood self-selection can lead to biased estimates of the association between the neighbourhood environment and behaviour. This means that effects could be over- or under-estimated, both of which have implications for public health policies related to neighbourhood (re)design. Therefore, it is important that methods to deal with neighbourhood self-selection are identified and reviewed. The aim of this review was to assess how neighbourhood self-selection is conceived and accounted for in the literature.

Inadequate administrative health data, suboptimal public health infrastructure, rapid and unplanned urbanization, environmental degradation, and poor penetration of information technology make the tracking of health and well-being of populations and their social determinants in the developing countries challenging. Technology-integrated comprehensive surveillance platforms have the potential to overcome these gaps.

Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine-acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I-BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I-BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors.

The aim of this study was to investigate the impact of bedside discharge education on activity levels and healthcare utilization for patients with acute coronary syndrome (ACS) in the first 30 days post-discharge. Knowledge recall and objective activity and location data were collected by global positioning systems (GPS). Participants were asked to carry the tracking applications (apps) for 30⁻90 days. Eighteen participants were recruited (6 metropolitan 12 rural) 61% ST elevation myocardial infarction (STEMI), mean age 55 years, 83% male. Recall of discharge education included knowledge of diagnosis (recall = 100%), procedures (e.g., angiogram = 40%), and comorbidities (e.g., hypertension = 60%, diabetes = 100%). In the first 30 days post-discharge, median steps per day was 2506 (standard deviation (SD) ± 369) steps (one participant completed 10,000 steps), 62% visited a general practitioner (GP) 16% attended cardiac rehabilitation, 16% visited a cardiologist, 72% a pharmacist, 27% visited the emergency department for cardiac event, and 61% a pathology service (blood tests). Adherence to using the activity tracking apps was 87%. Managing Big Data from the GPS and physical activity tracking apps was a challenge with over 300,000 lines of raw data cleaned to 90,000 data points for analysis. This study was an example of the application of objective data from the real world to help understand post-ACS discharge patient activity. Rates of access to services in the first 30 days continue to be of concern.

The metabolic protein alpha-methylacyl-CoA racemase (AMACR) is significantly overexpressed in prostate cancer compared to the normal prostate and other non-malignant tissue. Though an attractive target, there are no reports in the literature on leveraging the expression of AMACR for the molecular imaging of prostate cancer. Here, we used a molecular-genetic imaging strategy to exploit the transcriptional specificity of the AMACR promoter for the in vivo detection of prostate cancer using the reporter gene luciferase. We performed a stepwise truncation of the promoter and identified a 565 base pair minimal promoter for AMACR that retained both high activity and specificity. Following identification of the minimal promoter for AMACR, we used an advanced two-step transcriptional amplification system to maximize the promoter output. We showed that our optimized AMACR promoter can drive expression of luciferase for molecular imaging in subcutaneous xenograft models of androgen receptor-positive and androgen receptor-negative prostate cancer using a non-replicative adenovirus for gene delivery. Our results provide evidence that the AMACR promoter can be exploited to drive the cancer-specific expression of reporter genes and potentially even be incorporated into conditionally replicative adenoviruses for oncolytic therapy and other applications.

Presumed pathways from environments to cardiometabolic risk largely implicate health behaviour although mental health may play a role. Few studies assess relationships between these factors. This study estimated associations between area socioeconomic status (SES), mental health, diet, physical activity, and 10-year change in glycosylated haemoglobin (HbA1c), comparing two proposed path structures: 1) mental health and behaviour functioning as parallel mediators between area SES and HbA1c; and 2) a sequential structure where mental health influences behaviour and consequently HbA1c. Three waves (10 years) of population-based biomedical cohort data were spatially linked to census data based on participant residential address. Area SES was expressed at baseline using an established index (SEIFA-IEO). Individual behavioural and mental health information (Wave 2) included diet (fruit and vegetable servings per day), physical activity (meets/does not meet recommendations), and the mental health component score of the 36-item Short Form Health Survey. HbA1c was measured at each wave. Latent variable growth models with a structural equation modelling approach estimated associations within both parallel and sequential path structures. Models were adjusted for age, sex, employment status, marital status, education, and smoking. The sequential path model best fit the data. HbA1c worsened over time. Greater area SES was statistically significantly associated with greater fruit intake, meeting physical activity recommendations, and had a protective effect against increasing HbA1c directly and indirectly through physical activity behaviour. Positive mental health was statistically significantly associated with greater fruit and vegetable intakes and was indirectly protective against increasing HbA1c through physical activity. Greater SES was protective against increasing HbA1c. This relationship was partially mediated by physical activity but not diet. A protective effect of mental health was exerted through physical activity. Public health interventions should ensure individuals residing in low SES areas, and those with poorer mental health are supported in meeting physical activity recommendations.