Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Caspase-2 Cleavage of BID Is a Critical Apoptotic Signal Downstream of Endoplasmic Reticulum Stress▿

The accumulation of misfolded proteins stresses the endoplasmic reticulum (ER) and triggers cell death through activation of the multidomain proapoptotic BCL-2 proteins BAX and BAK at the outer mitochondrial membrane. The signaling events that connect ER stress with the mitochondrial apoptotic machinery remain unclear, despite evidence that deregulation of this pathway contributes to cell loss in many human degenerative diseases. In order to “trap” and identify the apoptotic signals upstream of mitochondrial permeabilization, we challenged Bax−/− Bak−/− mouse embryonic fibroblasts with pharmacological inducers of ER stress. We found that ER stress induces proteolytic activation of the BH3-only protein BID as a critical apoptotic switch. Moreover, we identified caspase-2 as the premitochondrial protease that cleaves BID in response to ER stress and showed that resistance to ER stress-induced apoptosis can be conferred by inhibiting caspase-2 activity. Our work defines a novel signaling pathway that couples the ER and mitochondria and establishes a principal apoptotic effector downstream of ER stress

Rationale and study protocol for the supporting children's outcomes using rewards, exercise and skills (SCORES) group randomized controlled trial: A physical activity and fundamental movement skills intervention for primary schools in low-income communities

Background: Many Australian children are insufficiently active to accrue health benefits and physical activity (PA) levels are consistently lower among youth of low socio-economic position. PA levels decline dramatically during adolescence and evidence suggests that competency in a range of fundamental movement skills (FMS) may serve as a protective factor against this trend. Methods/design:The Supporting Children's Outcomes Using Rewards Exercise and Skills (SCORES) intervention is a multi-component PA and FMS intervention for primary schools in low-income communities, which will be evaluated using a group randomized controlled trial.The socio-ecological model provided a framework for the 12-month intervention, which includes the following components: teacher professional learning, student leadership workshops (including leadership accreditation and rewards, e.g., stickers, water bottles), PA policy review, PA equipment packs, parental engagement via newsletters, FMS homework and a parent evening, and community partnerships with local sporting organizations. Outcomes will be assessed at baseline, 6- and 12-months. The primary outcomes are PA (accelerometers), FMS (Test of Gross Motor Development II) and cardiorespiratory fitness (multi-stage fitness test). Secondary outcomes include body mass index [using weight (kg)/height (m 2)], perceived competence, physical self-esteem, and resilience. Individual and environmental mediators of behavior change (e.g. social support and enjoyment) will also be assessed. The System for Observing Fitness Instruction Time will be used to assess the impact of the intervention on PA within physical education lessons. Statistical analyses will follow intention-to-treat principles and hypothesized mediators of PA behavior change will be explored. Discussion: SCORES is an innovative primary school-based PA and FMS intervention designed to support students attending schools in low-income communities to be more skilled and active. The findings from the study may be used to guide teacher pre-service education, professional learning and school policy in primary schools

Rationale and study protocol for the Supporting Children's Outcomes Using Rewards, Exercise and Skills (SCORES) group randomized controlled trial: A physical activity and fundamental movement skills intervention for primary schools in low-income communities

Background: Many Australian children are insufficiently active to accrue health benefits and physical activity (PA) levels are consistently lower among youth of low socio-economic position. PA levels decline dramatically during adolescence and evidence suggests that competency in a range of fundamental movement skills (FMS) may serve as a protective factor against this trend. Methods/design: The Supporting Children’s Outcomes Using Rewards Exercise and Skills (SCORES) intervention is a multi-component PA and FMS intervention for primary schools in low-income communities, which will be evaluated using a group randomized controlled trial. The socio-ecological model provided a framework for the 12-month intervention, which includes the following components: teacher professional learning, student leadership workshops (including leadership accreditation and rewards, e.g., stickers, water bottles), PA policy review, PA equipment packs, parental engagement via newsletters, FMS homework and a parent evening, and community partnerships with local sporting organizations. Outcomes will be assessed at baseline, 6- and 12-months. The primary outcomes are PA (accelerometers), FMS (Test of Gross Motor Development II) and cardiorespiratory fitness (multi-stage fitness test). Secondary outcomes include body mass index [using weight (kg)/height (m²)], perceived competence, physical self-esteem, and resilience. Individual and environmental mediators of behavior change (e.g. social support and enjoyment) will also be assessed. The System for Observing Fitness Instruction Time will be used to assess the impact of the intervention on PA within physical education lessons. Statistical analyses will follow intention-to-treat principles and hypothesized mediators of PA behavior change will be explored. Discussion: SCORES is an innovative primary school-based PA and FMS intervention designed to support students attending schools in low-income communities to be more skilled and active. The findings from the study may be used to guide teacher pre-service education, professional learning and school policy in primary schools

Rationale and study protocol for the supporting children’s outcomes using rewards, exercise and skills (SCORES) group randomized controlled trial: A physical activity and fundamental movement skills intervention for primary schools in low-income communities

Abstract Background Many Australian children are insufficiently active to accrue health benefits and physical activity (PA) levels are consistently lower among youth of low socio-economic position. PA levels decline dramatically during adolescence and evidence suggests that competency in a range of fundamental movement skills (FMS) may serve as a protective factor against this trend. Methods/design The Supporting Children’s Outcomes Using Rewards Exercise and Skills (SCORES) intervention is a multi-component PA and FMS intervention for primary schools in low-income communities, which will be evaluated using a group randomized controlled trial. The socio-ecological model provided a framework for the 12-month intervention, which includes the following components: teacher professional learning, student leadership workshops (including leadership accreditation and rewards, e.g., stickers, water bottles), PA policy review, PA equipment packs, parental engagement via newsletters, FMS homework and a parent evening, and community partnerships with local sporting organizations. Outcomes will be assessed at baseline, 6- and 12-months. The primary outcomes are PA (accelerometers), FMS (Test of Gross Motor Development II) and cardiorespiratory fitness (multi-stage fitness test). Secondary outcomes include body mass index [using weight (kg)/height (m2)], perceived competence, physical self-esteem, and resilience. Individual and environmental mediators of behavior change (e.g. social support and enjoyment) will also be assessed. The System for Observing Fitness Instruction Time will be used to assess the impact of the intervention on PA within physical education lessons. Statistical analyses will follow intention-to-treat principles and hypothesized mediators of PA behavior change will be explored. Discussion SCORES is an innovative primary school-based PA and FMS intervention designed to support students attending schools in low-income communities to be more skilled and active. The findings from the study may be used to guide teacher pre-service education, professional learning and school policy in primary schools. Trial registration Australian New Zealand Clinical Trials Registry No: ACTRN12611001080910</p