The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma

<p>Abstract</p> <p>Background</p> <p>Malignant brain tumors affect people of all ages and are the second leading cause of cancer deaths in children. While current treatments are effective and improve survival, there remains a substantial need for more efficacious therapeutic modalities. The ketogenic diet (KD) - a high-fat, low-carbohydrate treatment for medically refractory epilepsy - has been suggested as an alternative strategy to inhibit tumor growth by altering intrinsic metabolism, especially by inducing glycopenia.</p> <p>Methods</p> <p>Here, we examined the effects of an experimental KD on a mouse model of glioma, and compared patterns of gene expression in tumors vs. normal brain from animals fed either a KD or a standard diet.</p> <p>Results</p> <p>Animals received intracranial injections of bioluminescent GL261-luc cells and tumor growth was followed <it>in vivo</it>. KD treatment significantly reduced the rate of tumor growth and prolonged survival. Further, the KD reduced reactive oxygen species (ROS) production in tumor cells. Gene expression profiling demonstrated that the KD induces an overall reversion to expression patterns seen in non-tumor specimens. Notably, genes involved in modulating ROS levels and oxidative stress were altered, including those encoding cyclooxygenase 2, glutathione peroxidases 3 and 7, and periredoxin 4.</p> <p>Conclusions</p> <p>Our data demonstrate that the KD improves survivability in our mouse model of glioma, and suggests that the mechanisms accounting for this protective effect likely involve complex alterations in cellular metabolism beyond simply a reduction in glucose.</p

Feasibility and Acceptability of a Pilot Knowledge Translation Telementoring Program for Allied Health Professionals

Purpose: Knowledge translation (KT) in the health system is critical for the delivery of evidence-based practice. Supporting allied health professionals to plan and implement KT, using strategies that broadly reach across multiple geographical locations of the workforce, are needed. We piloted KT group telementoring via videoconference as an innovative solution to support and empower a vastly dispersed workforce. Methods: The 6-month Knowledge Translation Support Service (KTSS) involved monthly, one-hour, virtual group-based support of clinician-led KT projects within state-run hospital and health services. Supported by an independent facilitator, a panel of KT experts and health service leaders provided constructive critique and KT support for four projects from various disciplines (dietetics, nursing, occupational therapy, physiotherapy and social work) and health districts. Process evaluation included an assessment of program fidelity, dose delivered and engagement. Program acceptability (participants and panel members) was assessed after each session through online surveys. Effectiveness was captured by survey of KT confidence and qualitative interviews of participants perceived benefits of participation. Results: All project leads attended each meeting, with 1-2 specific projects discussed each month. On completion, participants reported high program satisfaction and felt that the KTSS met their expectations and learning needs. Overall the participants described beneficial gains with confidence in KT skills. Conclusions: The telementoring offered exposure to a breadth of expertise not normally accessible, successfully built a team environment in the virtual space and had a positive impact on project progression. Future directions include investing in scalability and sustainability of telementoring strategies for KT support

Genome-Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium.

ObjectivePopulations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry.MethodsLevels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis.ResultsIn the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2  = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT.ConclusionsPNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry

The ACS Nearby Galaxy Survey Treasury IV. The Star Formation History of NGC 2976

We present resolved stellar photometry of NGC 2976 obtained with the Advanced Camera for Surveys (ACS) as part of the ACS Nearby Galaxy Survey Treasury (ANGST) program. The data cover the radial extent of the major axis of the disk out to 6 kpc, or ~6 scale lengths. The outer disk was imaged to a depth of M_F606W ~ 1, and an inner field was imaged to the crowding limit at a depth of M_F606W ~ -1. Through detailed analysis and modeling of these CMDs we have reconstructed the star formation history of the stellar populations currently residing in these portions of the galaxy, finding similar ancient populations at all radii but significantly different young populations at increasing radii. In particular, outside of the well-measured break in the disk surface brightness profile, the age of the youngest population increases with distance from the galaxy center, suggesting that star formation is shutting down from the outside-in. We use our measured star formation history, along with H I surface density measurements, to reconstruct the surface density profile of the disk during previous epochs. Comparisons between the recovered star formation rates and reconstructed gas densities at previous epochs are consistent with star formation following the Schmidt law during the past 0.5 Gyrs, but with a drop in star formation efficiency at low gas densities, as seen in local galaxies at the present day. The current rate and gas density suggest that rapid star formation in NGC 2976 is currently in the process of ceasing from the outside-in due to gas depletion. This process of outer disk gas depletion and inner disk star formation was likely triggered by an interaction with the core of the M81 group >~1 Gyr ago that stripped the gas from the galaxy halo and/or triggered gas inflow from the outer disk toward the galaxy center.Comment: 22 pages, 14 figures, 2 tables, accepted for publication by Ap

The driver landscape of sporadic chordoma.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike