AKT mutant allele-specific activation dictates pharmacologic sensitivities.

AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.

OncoKB: A Precision Oncology Knowledge Base.

PURPOSE: With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. METHODS: OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature. RESULTS: To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. CONCLUSION: OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions.

The Effect of Age on the Prevalence of Obesity among US Youth with Autism Spectrum Disorder.

BACKGROUND: We sought to assess the association between age and the prevalence of obesity among children with and without autism spectrum disorder (ASD) in the 2011-2012 National Survey of Children's Health. METHODS: Analyses were restricted to 43,777 children, ages 10-17, with valid measures of parent-reported weight, height, and ASD status. Exploratory analyses describe the impact of sex, race/ethnicity, and household income on the relationship between age and obesity in ASD. RESULTS: Although the overall prevalence of obesity among children with ASD was significantly (p < 0.001) higher than among children without ASD (23.1% vs. 14.1%, 95% confidence interval for difference 3.6 to 14.4), child age significantly (p = 0.035) modified this difference. In a multivariable logistic regression analysis, adjusted for sex, race/ethnicity, and household income, the odds of obesity among children with ASD compared with children without ASD increased monotonically from ages 10 to 17 years. This pattern arose due to a consistently high prevalence of obesity among children with ASD and a decline in prevalence with advancing age among children without ASD. These findings were replicated using a propensity score analysis. Exploratory analyses suggested that the age-related change in obesity disparity between children with and without ASD may be further modified by sex, race/ethnicity, and household income. CONCLUSIONS: The patterns of prevalence observed with increasing age among children with and without ASD were unexpected. A better understanding of the etiological and maintenance factors for obesity in youth with ASD is needed to develop interventions tailored to the specific needs of these children.

Strategies for inclusion in play among children with physical disabilities in childcare centers: an integrative review.

The purpose of this integrative review was to examine strategies that facilitate inclusion in play among children with physical disabilities in childcare centers. Nine databases were systematically searched for peer reviewed empirical studies investigating inclusion strategies for play in childcare settings among preschoolers with physical disabilities. Nine studies met the inclusion criteria and were appraised using the McMaster Critical Review Forms. The inclusion approaches identified were grouped into relevant strategies during analysis. Two main strategies were identified: role of the adult facilitator and environmental factors. substrategies within the role of the adult facilitator included: customize approach for specific child's needs; adult facilitator self-awareness of presence; prompting and praise; and promote fairness, equity, and play interaction. Substrategies within the environmental factors included: physical setting; type of toys; and type of play activity. The findings suggest play inclusion strategies in the childcare environment. Therapists are encouraged to apply inclusion strategies to improve play opportunities for children with disabilities, but future research is necessary to confirm the effectiveness of these strategies using higher quality study designs.

Comparison of sedentary behaviors between children with autism spectrum disorders and typically developing children.

Time spent in sedentary behavior is largely due to time spent engaged with electronic screen media. Little is known about the extent to which sedentary behaviors for children with autism spectrum disorder differ from typically developing children. We used parental report to assess and compare time spent in sedentary behaviors for 53 children with autism spectrum disorder and 58 typically developing children aged 3-11 years. We also determined how sedentary behavior was related to child weight status (body mass index z-score). Overall, children with autism spectrum disorder spent an hour more in sedentary behaviors on weekdays compared to typically developing children (5.2 vs 4.2 h, p = 0.03), and most of this difference was due to screen time. The age- and sex-adjusted estimate of weekday total daily screen time was 1.6 h (typically developing) compared to 2.5 h (autism spectrum disorder, p = 0.004 for difference). A significant relationship between BMI z-score and total sedentary behavior time on weekend days was observed among young children with ASD, but not among TD children. The modest association between weekend sedentary behaviour time and BMI z-score among children with ASD suggests that sedentary behaiour is linked to relative weight status in these children. Further research is needed to confirm these findings and identify causal pathways.

Accuracy of Dietary Reference Intakes for determining energy requirements in girls.

BACKGROUND: The most recent Dietary Reference Intakes (DRIs) (2002) for energy were based on pooled data from convenience samples of individuals with energy expenditure determined by using doubly labeled water (DLW). To our knowledge, the accuracy of these intake estimates has not been assessed in children. OBJECTIVE: We assessed the accuracy of DRI prediction equations for determining daily energy needs in girls by comparing the individual-level prediction of estimated energy requirements with the measured value of total energy expenditure (TEE) from DLW, which is considered the gold standard. DESIGN: In this cross-sectional analysis, we measured the resting metabolic rate (RMR) by using indirect calorimetry and TEE by using DLW in 161 nonobese premenarcheal girls aged 8-12 y. The activity factor TEE/RMR was used to categorize the physical activity level used in DRI equations. RESULTS: We observed a strong linear relation between TEE by using DLW and estimated energy requirements predicted from DRI equations (Pearson's r = 0.78, P < 0.0001, R(2) = 0. 61). The DRI-predicted energy requirements underestimated measured TEE by ~120 kcal on average. The overall mean (±SD) error in the sample was -121.3 ± 163.9 kcal. The average (±SD) percentage error in the sample was -5.8 ± 7.9%. Seventy percent of participants had predicted TEE values ≤10% of measured TEE. CONCLUSIONS: DRI equations for girls predict well for the group. The use of these equations for individuals may result in the underestimation of energy requirements for a significant percentage of girls.

The association between childhood obesity and tooth eruption.

Obesity is a growth-promoting process as evidenced by its effect on the timing of puberty. Although studies are limited, obesity has been shown to affect the timing of tooth eruption. Both the timing and sequence of tooth eruption are important to overall oral health. The purpose of this study was to examine the association between obesity and tooth eruption. Data were combined from three consecutive cycles (2001-2006) of the National Health and Nutrition Examination Survey (NHANES) and analyzed to examine associations between the number of teeth erupted (NET) and obesity status (BMI z-score >95th percentile BMI relative to the Centers for Disease Control and Prevention (CDC) growth reference) among children 5 up to 14 years of age, controlling for potential confounding by age, gender, race, and socioeconomic status (SES). Obesity is significantly associated with having a higher average NET during the mixed dentition period. On average, teeth of obese children erupted earlier than nonobese children with obese children having on average 1.44 more teeth erupted than nonobese children, after adjusting for age, gender, and race/ethnicity (P < 0.0001). SES was not a confounder of the observed associations. Obese children, on average, have significantly more teeth erupted than nonobese children after adjusting for gender, age, and race. These findings may have clinical importance in the area of dental and orthodontic medicine both in terms of risk for dental caries due to extended length of time exposed in the oral cavity and sequencing which may increase the likelihood of malocclusions.

Occurrence and timing of childhood overweight and mortality: findings from the Third Harvard Growth Study.

OBJECTIVE: To assess the mortality experience of participants in the Third Harvard Growth Study (1922-1935) who provided ≥ 8 years of growth data. STUDY DESIGN: A total of 1877 participants provided an average of 10.5 body mass index measurements between age 6 and 18 years. Based on these measurements, the participants were classified as ever overweight or ever >85th percentile for height in childhood. Age at peak height velocity was used to indicate timing of overweight relative to puberty. Relative risks of all-cause and cause-specific mortality according to measures of childhood growth were estimated using Cox proportional hazards survival analysis. RESULTS: For women, ever being overweight in childhood increased the risks of all-cause and breast cancer death; the risk of death from ischemic heart disease was increased in men. Men with a first incidence of overweight before puberty were significantly more likely to die from ischemic heart disease; women in the same category were more likely to die from all causes and from breast cancer. CONCLUSION: We find evidence of long-term effects of having ever been overweight, with some evidence that incidence before puberty influences the pattern of risk.

Activity, inactivity, and screen time in relation to weight and fatness over adolescence in girls.

OBJECTIVE: The impact of activity and inactivity on relative weight and fatness change are best evaluated longitudinally. We examined the longitudinal relationship of physical activity, inactivity, and screen time with relative weight status and percentage body fat (%BF) and explored how it differed by parental overweight status. RESEARCH METHODS AND PROCEDURES: Non-obese pre-menarcheal girls (173), 8 to 12 years old, were followed until 4 years post-menarche. %BF, BMI z-score, and time spent sleeping, sitting, standing, walking, and in vigorous activity were assessed annually. We developed a physical activity index to reflect time and intensity of activity. Inactivity was defined as the sum of time spent sleeping, sitting, and standing. Screen time was defined as time spent viewing television, videotapes, or playing video games. Parental overweight was defined as at least one parent with BMI>25. RESULTS: In separate linear mixed effects models, activity, inactivity, and screen time were unrelated to BMI z-score longitudinally, with and without accounting for parental overweight. After controlling for parental overweight, activity was inversely related (p<0.001), and inactivity was directly related (p<0.035) to increased %BF longitudinally. Screen time was unrelated to %BF change. With stratification for parental overweight, effects of activity and inactivity on %BF were observed only among girls with at least one overweight parent. DISCUSSION: In this cohort of initially non-overweight girls, activity and inactivity were related to accrual of BF over adolescence, particularly among children with at least one overweight parent. These results suggest that girls with a family history of overweight represent a target population of high priority for interventions around physical activity and inactivity.

Childhood overweight and maturational timing in the development of adult overweight and fatness: the Newton Girls Study and its follow-up.

OBJECTIVE: Although several studies have suggested that early menarche is associated with the development of adult overweight, few have accounted for childhood overweight before menarche. STUDY DESIGN: A 30-year follow-up of the original participants in the Newton Girls Study, a prospective study of development in a cohort of girls followed through menarche, provided data on premenarcheal relative weight and overweight (BMI >85th percentile), prospectively obtained age at menarche, self-reported adult BMI, overweight (BMI > 25), obesity (BMI > 30) and, for a subset of participants, percentage body fat by dual-energy x-ray absorptiometry. RESULTS: Of the 448 women who participated in the adult follow-up at a mean age of 42.1 years (SD: 0.76 years), 307 had childhood data with which to characterize premenarcheal and menarcheal weight status and age at menarche. After a follow-up of 30.1 years (SD: 1.4 years), reported BMI was 23.4 (4.8), 28% were overweight, and 9% were obese. In multivariate linear and logistic-regression analyses, almost all of the influence on adult weight status was a result of premenarcheal weight status (model R2 = 0.199). Inclusion of a variable to reflect menarcheal timing provided very little additional information (model R2 = 0.208). Girls who were overweight before menarche were 7.7 times more likely to be overweight as adults (95% confidence interval: 2.3, 25.8), whereas early menarche (at < or = 12 years of age) did not elevate risk (odds ratio: 1.3, 95% confidence interval: 0.66, 2.43). A similar pattern of results was observed when percentage body fat in adulthood was evaluated. CONCLUSIONS: The apparent influence of early maturation on adult female overweight is largely a result of the influence of elevated relative weight on early maturation. Interventions to prevent and treat overweight should focus on girls before they begin puberty.

Relation of body mass index and body fatness to energy expenditure: longitudinal changes from preadolescence through adolescence.

BACKGROUND: Although it is widely accepted that weight gain results when energy intake exceeds energy expenditure (EE), how reduced EE contributes to the development of obesity remains unclear. OBJECTIVE: We tested the hypothesis that reduced EE in the premenarcheal period in girls constitutes a risk factor for an increase in relative weight [body mass index (BMI) z score] and percentage of body fat (%BF) during adolescence. DESIGN: We measured EE at study entry in 196 premenarcheal nonobese girls. Resting metabolic rate (RMR) was measured by indirect calorimetry. Total energy expenditure (TEE) was measured by the doubly labeled water method. Activity energy expenditure (AEE) was calculated from RMR and TEE. After the baseline study, girls were followed annually until 4 y after menarche (x+/- SD: 7.1 +/- 2.6 y). At each visit, height, weight, and %BF by bioelectrical impedance were measured. Girls also completed annual food-frequency and activity questionnaires. Linear mixed effects modeling was used to evaluate the longitudinal relation between BMI z score and %BF and measures of baseline EE. RESULTS: We found no significant relation in change in %BF with RMR, AEE, or TEE. We observed a small positive relation between BMI z score and AEE and TEE (P < 0.05) but no significant relation with RMR. When we stratified by parental overweight, the findings were unchanged for RMR. TEE and AEE were positively related to BMI z score in girls of overweight parents. CONCLUSIONS: Our findings suggest that EE in the premenarcheal period is not a risk factor for increases in %BF or BMI z score in girls during adolescence.

Energy-dense snack food intake in adolescence: longitudinal relationship to weight and fatness.

OBJECTIVE: The longitudinal relationship between the consumption of energy-dense snack (EDS) foods and relative weight change during adolescence is uncertain. Using data from the Massachusetts Institute of Technology Growth and Development Study, the current analysis was undertaken to examine the longitudinal relationship of EDS food intake with relative weight status and percentage body fat and to examine how EDS food consumption is related to television viewing. RESEARCH METHODS AND PROCEDURES: One hundred ninety-six nonobese premenarcheal girls 8 to 12 years old were enrolled between 1990 and 1993 and followed until 4 years after menarche. At each annual follow-up visit, data were collected on percentage body fat (%BF), BMI z score, and dietary intake. Categories of EDS foods considered were baked goods, ice cream, chips, sugar-sweetened soda, and candy. RESULTS: At study entry, girls had a mean +/- SD BMI z score of -0.27 +/- 0.89, consumed 2.3 +/- 1.7 servings of EDS foods per day, and consumed 15.7 +/- 8.1% of daily calories from EDS foods. Linear mixed effects modeling indicated no relationship between BMI z score or %BF and total EDS food consumption. Soda was the only EDS food that was significantly related to BMI z score over the 10-year study period, but it was not related to %BF. In addition, a significant, positive relationship was observed between EDS food consumption and television viewing. DISCUSSION: In this cohort of initially nonobese girls, overall EDS food consumption does not seem to influence weight status or fatness change over the adolescent period.

A longitudinal comparison of body composition by total body water and bioelectrical impedance in adolescent girls.

Previous studies have assessed the ability of bioelectrical impedance analysis (BIA) to estimate body composition cross-sectionally, but less is known about the ability of BIA to detect changes in body composition longitudinally over the adolescent growth period. Body composition was assessed by isotopic dilution of H(2)(18)O and BIA in 196 initially nonobese girls enrolled in a longitudinal study. Two prediction equations for use in our population of girls were developed, one for use premenarcheally and one for use postmenarcheally. We compared estimates from our equation with those derived from several published equations. Using longitudinal data analysis techniques, we estimated changes in fat-free mass (FFM) and percentage body fat (%BF) over time from BIA, compared with changes in FFM and % BF estimated by H(2)(18)O. A total of 422 measurements from 196 girls were available for analysis. Of the participants, 26% had one measurement of body composition, 43% had two measurements of body composition and 31% had three or more measurements of body composition. By either H(2)(18)O or BIA, the mean %BF at study entry was 23% (n = 196) and the mean %BF at 4 y postmenarche was 27% (n = 133). In our cohort, the best predictive equations to estimate FFM by BIA were: PREMENARCHE: FFM = -5.508 + (0.420 x height(2)/resistance) + (0.209 x weight) + (0.08593 x height) + (0.515 x black race) - (0.02273 x other race). POSTMENARCHE: FFM = -11.937 + (0.389 x height(2)/resistance) + (0.285 x weight) + (0.124 x height) + (0.543 x black race) + (0.393 x other race). Overall, we found that BIA provided accurate estimates of the change in both FFM and %BF over time.