Predicting Energy Expenditure from Accelerometry Counts in Adolescent Girls

Calibration of accelerometer counts against oxygen consumption to predict energy expenditure has not been conducted in middle school girls. We concurrently assessed energy expenditure and accelerometer counts during physical activities on adolescent girls to develop an equation to predict energy expenditure

Comparison of Two Approaches to Structured Physical Activity Surveys of Adolescents

Purpose - To compare the test-retest reliability, convergent validity, and overall feasibility/usability of activity-based (AB) and time-based (TB) approaches for obtaining self-reported moderate-to-vigorous physical activity (MVPA) from adolescents. Methods - Adolescents (206 females and 114 males) completed two 3-d physical activity recalls using the AB and TB surveys, which contained identical lists of physical activities. The participants wore an MTI Actigraph® accelerometer for the same period. Results - The TB instrument took about 3 min longer to complete (P=0.022). Overall 2-d test-retest correlations for MVPA were similar for the two surveys (r=0.676 and 0.667), but the girls had higher reliability on the AB survey than the boys (girls: r=0.713; boys: r=0.568). The overall 3-d correlations for MVPA surveys and Actigraph counts varied by gender (girls: AB=0.265 vs TB=0.314; boys: AB=0.340 vs TB=0.277). Correlations for vigorous physical activity and Actigraph counts were higher for the AB than for the TB (r=0.281 vs 0.162). As the interval between completing the surveys and the days being recalled increased, reliability and validity were lower, especially for the AB survey. Conclusion - For both genders, either approach is acceptable for obtaining MVPA information on a single day, but the TB approach appears to be slightly favored over the AB approach for obtaining multiple days of MVPA. A 3-d recall period appears to be too long for accurate recall of MVPA information from either instrument. For both genders, the surveys overestimate activity levels; thus, self-reports should be supplemented with objective data

Genomic profile of advanced breast cancer in circulating tumour DNA.

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities

Comparative transcriptome profiling of amyloid precursor protein family members in the adult cortex

<p>Abstract</p> <p>Background</p> <p>The β-amyloid precursor protein (APP) and the related β-amyloid precursor-like proteins (APLPs) undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that Aβ accumulation is a central trigger for Alzheimer's disease, the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsα ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The γ-secretase-generated APP intracellular domain (AICD) functions as a transcriptional regulator in heterologous reporter assays although its role for endogenous gene regulation has remained controversial.</p> <p>Results</p> <p>To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators, we performed DNA microarray transcriptome profiling of prefrontal cortex of adult wild-type (WT), APP knockout (APP^-/-), APLP2 knockout (APLP2^-/-) and APPsα knockin mice (APP^α/α) expressing solely the secreted APPsα ectodomain. Biological pathways affected by the lack of APP family members included neurogenesis, transcription, and kinase activity. Comparative analysis of transcriptome changes between mutant and wild-type mice, followed by qPCR validation, identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity-related genes that were both down-regulated in knockout cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including <it>Bace1</it>, <it>Kai1</it>, <it>Gsk3b</it>, <it>p53</it>, <it>Tip60</it>, and <it>Vglut2</it>. Only <it>Egfr </it>was slightly up-regulated in APLP2^-/-mice. Comparison of APP^-/-and APP^α/αwith wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2^-/-on different genetic backgrounds revealed that background-related transcriptome changes may dominate over changes due to the knockout of a single gene.</p> <p>Conclusion</p> <p>Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells.</p

Predicting energy expenditure from accelerometry counts in adolescent girls

Calibration of accelerometer counts against oxygen consumption to predict energy expenditure has not been conducted in middle school girls. We concurrently assessed energy expenditure and accelerometer counts during physical activities on adolescent girls to develop an equation to predict energy expenditure

Genomic profile of advanced breast cancer in circulating tumour DNA.

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities

Comparison of two approaches to structured physical activity surveys for adolescents

To compare the test-retest reliability, convergent validity, and overall feasibility/usability of activity-based (AB) and time-based (TB) approaches for obtaining self-reported moderate-to-vigorous physical activity (MVPA) from adolescents

Abstract PS5-02: Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial

Abstract Background: Early changes in circulating tumour DNA (ctDNA) levels may identify which patients respond to therapy earlier than imaging, with ctDNA levels falling rapidly in patients who respond to therapy. The plasmaMATCH trial assessed the utility of ctDNA testing with an error-corrected 73-gene targeted panel (Guardant360, Guardant Health) to allocate patients to four mutation matched therapy cohorts. ESR1-extended fulvestrant (A), HER2-neratinib +/- fulvestrant (B), AKT1-capivasertib + fulvestrant (C), AKT basket-capivasertib (D). Here, we report paired baseline and early on treatment ctDNA analysis from plasmaMATCH, to establish the optimal criteria for predicting progression free survival (PFS). Methods: In plasmaMATCH treatment cohorts, plasma samples were collected for ctDNA analysis pre-treatment at cycle 1-day 1 (C1D1) and cycle 2-day 1 (C2D1) timepoints, and sequenced with the Guardant 360 assay. Patients were included if they had a minimum of 14 days of treatment in the first cycle. Multiple different methods were investigated to integrate variant allele fractions (VAF) of mutations identified at each timepoint to estimate the level of ctDNA, including maximum VAF, mean VAF and weighted mean VAF, and weighted mean VAF of clonal mutations at C1D1. Variants with a VAF &amp;lt;0.3%, set as the limit of detection, in C1D1 were excluded. Genes frequently mutated in CHIP were excluded (GNAS, JAK2, IDH1, IDH2 and ATM) from the weighted mean VAF of clonal mutations method. The circulating DNA ratio (CDR) was calculated as the ratio of C2D1 level relative to C1D1 level. The optimal cut-point for predicting PFS was assessed by fitting a range of cutpoints for each VAF integration method, identifying the cut-point with the highest Harrell’s C-index. Results: A total of 142 patients were enrolled into plasmaMATCH cohorts A-D, 79 patients had samples sent for paired C1D1-C2D1 plasma ctDNA sequencing, 1 failed sequencing and 1 insufficient treatment, and 77 (54%) patients had assessable C1D1-C2D1 plasma ctDNA sequencing results (45 cohort A, 12 cohort B, 12 cohort C, 8 cohort D). A weighted mean of clonal mutations in C1D1 ctDNA sequencing was the optimal method for integrating VAF, with peak C-Index 0.67. At the optimal C-index cutoff of 0.132, median PFS with high ctDNA CDR was 2.4 months (95% CI 2.0-3.7) and with suppressed ctDNA CDR was 9.9 months (95% CI 7.0-13.7) (HR 4.3, 95% CI 2.4-7.6, p&amp;lt;0.0001). Early changes in ctDNA level were also predictive in cohorts A extended dose fulvestrant alone (HR 5.8, 95% CI 2.2-16, p=0.0001) and cohorts B-D of targeted therapy (HR 3.8, 95% CI 1.7-8.6, p=0.00063). In analysis that was not pre-planned, patients with undetectable ctDNA at C2D1 had a particularly good outcome (p&amp;lt;0.0001, table 1). Conclusions: We identify an optimal methodology for assessing early dynamic changes in ctDNA that predicts treatment efficacy in patients with metastatic breast cancer. This methodology will require validation in independent data-sets, and if validated would allow trials of adapting therapy on the basis of early ctDNA dynamics. Table 1ctDNA dynamics categoryMedian PFS months (95%CI)6-month PFSORRUndetectable (N=11) CDR=018.2 (10.2-NA)91%9/11 (82%)Suppressed (N=14) CDR &amp;lt;0.132 and &amp;gt;05.4 (4.6-NA)48%6/14 (43%)High (N=52) CDR &amp;gt;=0.1322.4 (2.0-3.7)8%4/52 (8%) Citation Format: Javier Pascual, Rosalind J Cutts, Belinda Kingston, Sarah Hrebien, Lucy S Kilburn, Sarah Kernaghan, Laura Moretti, Katie Wilkinson, Andrew M Wardley, Iain R Macpherson, Richard D Baird, Rebecca Roylance, Michael Hubank, Giselle Walsh, Iris Faull, Kimberly C Banks, Richard B Lanman, Isaac Garcia-Murillas, Judith M Bliss, Alistair Ring, Nicholas C Turner. Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-02.</jats:p

Validity of Social-Cognitive Measures for Physical Activity in Middle-School Girls

Objective The factorial validity and measurement equivalence/invariance of scales used to measure social-cognitive correlates of physical activity among adolescent girls were examined. Methods Confirmatory factor analysis was applied to questionnaire responses obtained from a multi-ethnic sample (N = 4885) of middle-school girls from six regions of the United States. A cohort of 1893 girls completed the scales in both sixth and eighth grades, allowing longitudinal analysis. Results Theoretically and statistically sound models were developed for each scale, supporting the factorial validity of the scales in all groups. Multi-group and longitudinal invariance was confirmed across race/ethnicity groups, age within grade, BMI categories, and the 2-year period between grades. Conclusions The scores from the scales provide valid assessments of social-cognitive variables that are putative mediators or moderators of change in physical activity. The revised scales can be used in observational studies of change or interventions designed to increase physical activity among girls during early adolescence