Physical Activity and Food Environments in and around Schools: A Case Study in Regional North-West Tasmania.

A better understanding of the physical activity (PA) infrastructure in schools, the walkability of neighborhoods close to schools, and the food environments around schools, particularly in rural, socioeconomically challenged areas such as the North-West (NW) of Tasmania, could be important in the wider effort to improve the health of school-age children. Accordingly, this research aimed to assess PA resources, walkability, and food environments in and around schools in three socioeconomically disadvantaged, regional/rural Local Government Areas (LGAs) of Tasmania, Australia. A census of schools (including assessment of the PA infrastructure quality within school grounds), a walkability assessment, and a census of food outlets surrounding schools (through geospatial mapping) were executed. Most of the schools in the study region had access to an oval, basketball/volleyball/netball court, and free-standing exercise equipment. In all instances (i.e., regardless of school type), the quality of the available infrastructure was substantially higher than the number of incivilities observed. Most schools also had good (i.e., within the first four deciles) walkability. Numerous food outlets were within the walking zones of all schools in the study region, with an abundance of food outlets that predominantly sold processed unhealthy food.

A Spatial Analysis of Access to Physical Activity Infrastructure and Healthy Food in Regional Tasmania.

Prevalence of physical inactivity and obesity continues to increase in regional areas such as North-West (NW) Tasmania and show no signs of abating. It is possible that limited access to physical activity infrastructure (PAI) and healthier food options are exacerbating the low levels of habitual physical activity and obesity prevalence in these communities. Despite a burgeoning research base, concomitant exploration of both physical activity and food environments in rural and regional areas remain scarce. This research evaluated access (i.e., coverage, variety, density, and proximity) to physical activity resources and food outlets in relation to socioeconomic status (SES) in three NW Tasmanian communities. In all three study areas, the PAI and food outlets were largely concentrated in the main urban areas with most recreational tracks and natural amenities located along the coastline or river areas. Circular Head had the lowest total number of PAI (n = 43) but a greater proportion (30%) of free-to-access outdoor amenities. There was marked variation in accessibility to infrastructure across different areas of disadvantage within and between sites. For a considerable proportion of the population, free-to-access natural amenities/green spaces and recreational tracks (73 and 57%, respectively) were beyond 800 m from their households. In relation to food accessibility, only a small proportion of the food outlets across the region sells predominantly healthy (i.e., Tier 1) foods (~6, 13, and 10% in Burnie, Circular Head and Devonport, respectively). Similarly, only a small proportion of the residents are within a reasonable walking distance (i.e., 5-10 min walk) from outlets. In contrast, a much larger proportion of residents lived close to food outlets selling predominantly energy-dense, highly processed food (i.e., Tier 2 outlets). Circular Head had at least twice as many Tier 1 food stores per capita than Devonport and Burnie (0.23 vs. 0.10 and 0.06; respectively) despite recording the highest average distance (4.35 and 5.66 km to Tier 2/Tier 1 stores) to a food outlet. As such, it is possible that both food and physical activity environment layouts in each site are contributing to the obesogenic nature of each community.

EIF1AX and NRAS Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas.

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res; 77(16); 4268-78. ©2017 AACR.

Whole-genome characterization of chemoresistant ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Rescue of the Friedreich ataxia knockout mutation in transgenic mice containing an FXN-EGFP genomic reporter.

Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. We previously generated BAC-based transgenic mice containing an FXN-EGFP genomic reporter construct in which the EGFP gene is fused in-frame immediately following the final codon of exon 5a of the human FXN gene. These transgenic mice were mated with mice heterozygous for a knockout mutation of the murine Fxn gene, to generate mice homozygous for the Fxn knockout mutation and hemizygous or homozygous for the human transgene. Rescue of the embryonic lethality that is associated with homozygosity for the Fxn knockout mutation was observed. Rescue mice displayed normal behavioral and histological parameters with normal viability, fertility and life span and without any signs of aberrant phenotype. Immunoblotting demonstrated the production of full-length frataxin-EGFP fusion protein that appears to act as a bifunctional hybrid protein. This study shows frataxin replacement may be a viable therapeutic option. Further, these mice should provide a useful resource for the study of human FXN gene expression, frataxin function, the evaluation of pharmacologic inducers of FXN expression in a whole-animal model and provide a useful source of cells for stem cell transplantation studies.

c-MYC coordinately regulates ribosomal gene chromatin remodeling and Pol I availability during granulocyte differentiation.

Loss of c-MYC is required for downregulation of ribosomal RNA (rRNA) gene (rDNA) transcription by RNA Polymerase I (Pol I) during granulocyte differentiation. Here, we demonstrate a robust reduction of Pol I loading onto rDNA that along with a depletion of the MYC target gene upstream binding factor (UBF) and a switch from epigenetically active to silent rDNA accompanies this MYC reduction. We hypothesized that MYC may coordinate these mechanisms via direct regulation of multiple components of the Pol I transcription apparatus. Using gene expression arrays we identified a 'regulon' of Pol I factors that are both downregulated during differentiation and reinduced in differentiated granulocytes upon activation of the MYC-ER transgene. This regulon includes the novel c-MYC target genes RRN3 and POLR1B. Although enforced MYC expression during granulocyte differentiation was sufficient to increase the number of active rRNA genes, its activation in terminally differentiated cells did not alter the active to inactive gene ratio despite increased rDNA transcription. Thus, c-MYC dynamically controls rDNA transcription during granulocytic differentiation through the orchestrated transcriptional regulation of core Pol I factors and epigenetic modulation of number of active rRNA genes.

Evaluation of an FRDA-EGFP genomic reporter assay in transgenic mice.

Friedreich ataxia is an autosomal recessive neurodegenerative disorder caused by a GAA trinucleotide expansion in the first intron of the Friedreich ataxia gene (FRDA) that causes reduced synthesis of frataxin, a mitochondrial protein likely to be involved in biosynthesis of iron-sulfur clusters. This leads to increased oxidative stress, progressive loss of large sensory neurons, and hypertrophic cardiomyopathy. To elucidate the mechanisms regulating FRDA expression and to develop an in vivo assay for agents that might upregulate FRDA expression in a therapeutically relevant manner, we have generated transgenic mice with a BAC genomic reporter construct consisting of an in-frame fusion between FRDA and the gene coding for enhanced green fluorescent protein (EGFP). Production of full-length frataxin-EGFP fusion protein was demonstrated by immunoblotting. EGFP expression was observed as early as day E3.5 of development. Most tissues of adult transgenic mice were fluorescent. The level of FRDA-EGFP expression in peripheral blood, bone marrow, and cells obtained from enzymatically disaggregated tissues was quantitated by flow cytometry. There was a twofold increase in EGFP expression in mice homozygous for the transgene when compared to hemizygous mice. These transgenic mice are a valuable tool for the examination of spatial and temporal aspects of FRDA gene expression and for the preclinical evaluation of pharmacological inducers of FRDA expression in a whole-animal model. In addition, tissues from these mice should also be valuable for stem cell transplantation studies.