Combining AZD8931, a novel EGFR/HER2/HER3 signalling inhibitor, with AZD5363 limits AKT inhibitor induced feedback and enhances antitumour efficacy in HER2-amplified breast cancer models.

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling network is frequently de-regulated in breast cancer and has been shown to mediate resistance to anti-HER2 agents. Whilst constitutive activation of this pathway is emerging as a marker of sensitivity to various PI3K pathway inhibitors, activity of these agents in the clinic may be limited by the presence of feedback loops, leading to reactivation of receptor tyrosine kinases, such as HER2/HER3. To determine whether inhibition of HER2 could increase the efficacy of AZD5363, a novel AKT inhibitor, a panel of breast cancer cells was dosed with AZD5363 in combination with AZD8931, an inhibitor of EGFR/HER2/HER3 signalling. We show that the combined treatment resulted in synergistic growth inhibition and enhanced cell death, specifically in the HER2-amplified cell lines. Investigation of the mechanism by western blot analysis revealed that the addition of AZD8931 prevented the induction of HER2/HER3 phosphorylation induced by AZD5363 and resulted in concomitant inhibition of both the PI3K/AKT/mTOR and ERK signalling pathways and induction of apoptosis. Using the HCC1954 xenograft model, which is resistant to trastuzumab, we show that the combination of AZD5363 and AZD8931 is more efficacious than either agent alone, resulting in profound tumour regressions. We conclude that the activity of AZD5363 in HER2-amplified breast cancer cells is enhanced by the addition of AZD8931 and that dual targeting of AKT and EGFR/HER2/HER3 signalling is an attractive treatment option to be explored in the clinic.

Examination of the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) Factor Structure in a Sample of Pregnant Smokers.

INTRODUCTION: Smoking during pregnancy poses known risks to fetal and infant development. Women who continue to smoke during pregnancy exhibit higher levels of nicotine dependence than women who quit. Increased understanding of the construct of nicotine dependence in pregnant smokers may aid in the development of effective treatments. Research has suggested that nicotine dependence is a multifaceted construct, driven not only by withdrawal and tolerance processes, but also by reinforcement, sensory, and contextual processes. The Wisconsin inventory of smoking dependence motives (WISDM-68) assesses 13 varied smoking motives in order to assess processes that may lead to nicotine dependence. METHODS: The factor structure of the WISDM-68 was explored using an ethnically diverse sample of 294 pregnant women who had been screened and/or enrolled in a smoking cessation treatment study. Confirmatory analyses were conducted with previously published models. An exploratory factor analysis and exploratory structural equation modeling (ESEM) were conducted to develop and validate a measurement model for the WISDM-68 in this sample. RESULTS: Previously established models were not a good fit for the present data. Using ESEM, a 9-factor model exhibiting both predictive and concurrent validity emerged. Two factors predicted abstinence 6 months posttreatment. Several factors were associated with smoking heaviness, the Fagerström test for cigarette dependence and time to first cigarette. CONCLUSIONS: In contrast to previously published studies, a 9-factor model best characterizes the WISDM in the present sample. These findings may reflect smoking motivations unique to young, pregnant women who continue to smoke during pregnancy.

Characterization and prediction of sexual and nonsexual recidivism among adjudicated juvenile sex offenders.

Estimating the risk of sexual recidivism for a juvenile sex offender is essential in order to protect public safety by identifying and evaluating high risk adolescents and to ensure the rights and welfare of juvenile offenders who will not likely reoffend. Empirically validated risk assessment methods are needed to aid in the classification and treatment of juvenile sex offenders. The present study utilized a dataset collected by Maricopa County, AZ, and aggregated by the National Juvenile Court Data Archive. The purpose of the study was to evaluate and characterize risk factors for juveniles who have been charged with a sexual offense in order to determine the predictive utility of these factors for subsequent offending, as well as offense trajectory, and to evaluate risk factors for nonsexual offenders who have committed crimes of various severities. The results of the present study show the strongest individual predictors of sexual recidivism to be prior nonsexual offending, prior sexual offending, hands-off offending, offending against a child, younger school grade/age at time of initial offense, Asian or Hispanic ethnicity, and not attending school. A preliminary screening measure was developed from the seven positive risk factors, and ROC analysis produced an AUC indicating moderate predictive utility in discriminating between juvenile sex offenders who would sexually reoffend and those who would not.

Examining the interpersonal-psychological theory of suicide in an inpatient veteran sample.

Suicide among veterans is a pressing public health concern. The interpersonal-psychological theory of suicide proposes that perceived burdensomeness and thwarted belongingness lead to suicidal desire, whereas the acquired capability for suicide leads to suicide attempt in the presence of suicidal desire (Joiner, 2005). Two hypotheses derived from the interpersonal-psychological theory of suicide were tested in 185 veterans (96 women) entering inpatient psychiatric treatment. Burdensomeness and its interaction with belongingness significantly predicted current suicidal ideation. The three-way interaction between burdensomeness, belongingness, and acquired capability did not significantly predict number of past suicide attempts. Clinical implications and directions for future research are discussed.

Evaluation of trauma characteristics as predictors of attrition from cognitive-behavioral therapy for child victims of violence.

Little research has investigated psychotherapy attrition among child victims of violence, and no studies have evaluated the role of trauma characteristics (e.g., level of threat or injury, trauma frequency, perpetrator relationship, victim type, and trauma type). The current study evaluated premature psychotherapy termination with 134 child victims (ages 5-19 years) who were referred for exposure-based cognitive-behavioral therapy. Results indicated that premature treatment termination was associated with children who experienced (a) a single incident of trauma (compared to multiple), (b) neither life threat nor physical injury during the victimization, (c) and an incident that was perpetrated by an older child compared to a parental figure. Certain trauma characteristics may be important factors for identifying children at risk for terminating treatment prematurely.

AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.

The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (approximately 1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 micromol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials.

The use of symptom severity measured just before termination to predict child treatment dropout.

The current study examined indices of trauma-related symptom severity as predictors of dropout from exposure-based cognitive behavioral therapy in a sample of 99 child and adolescent trauma victims. The investigation incorporated measures of symptom severity at two time points: pretreatment and just before termination. The results indicated that a model with symptom severity measured just before termination was significantly associated with the number of attended sessions; however, a model with the symptom-severity indices measured at pretreatment was nonsignificant. In addition, a significant main effect indicated that increased avoidance behavior measured just before termination was related to fewer treatment sessions. Further analyses also suggested that higher severity of intrusion and depression measured just before termination was correlated with fewer treatment sessions. The results support the idea that more immediate distress may be related to treatment dropout. Implications for the research and practice of exposure therapy for child trauma are discussed.

Quality of life in Mexican-American children following a weight management program.

OBJECTIVE: The objective was to evaluate quality of life (QOL) in at-risk-for-overweight and overweight Mexican-American children after participating in 6 months of intensive weight management or self-help. RESEARCH METHODS AND PROCEDURES: Eighty sixth- and seventh-grade at-risk-for-overweight (BMI >or=85th to <95th percentile) and overweight (BMI >or=95th percentile) Mexican-American children were randomly assigned to either intensive instructor-led intervention (ILI) or self-help (SH). The ILI condition included daily participation for 12 weeks in a school-based program comprised of nutrition education, physical activity, and behavior modification, followed by ongoing monthly maintenance. QOL was assessed at baseline and 6 months via child self-report PedsQL. QOL outcomes were compared across treatment groups, and the impact of change in zBMI on change in QOL was evaluated. RESULTS: Children in the ILI condition not only achieved significantly greater weight loss (zBMI, -0.13 +/- 0.14; p < 0.001) but also significantly greater physical QOL improvements than those in the SH condition at 6 months (p < 0.05). Furthermore, physical QOL increases were associated with zBMI reduction (p < 0.05). However, neither psychosocial nor total QOL was significantly impacted by intervention or zBMI change. DISCUSSION: These findings show that even modest decreases in zBMI after weight management result in improved physical QOL in Mexican-American children. These results illustrate the clear need to include evaluation of QOL in the process of identifying effective weight management programs.

Ethnic differences in symptom presentation of sexually abused girls.

Although researchers have begun to examine the issue of ethnic and cultural factors in childhood sexual abuse (CSA), relatively little has been done to look at possible ethnic and cultural differences in psychological symptoms related to CSA. This study investigated the relationship between ethnicity and symptom presentation among Hispanic, African American, and Caucasian sexually abused girls. The study examined the relationship between ethnicity and depression, ethnicity and post-trauma intrusive symptoms, and ethnicity and post-trauma avoidance symptoms. Results indicated that African American girls had significantly higher levels of post-trauma avoidance symptoms than Hispanic girls, but not Caucasian girls. No significant differences were found between ethnic groups for depression or intrusive symptoms.