Carol Tan

Loss of TAK1 increases cell traction force in a ROS-dependent manner to drive epithelial-mesenchymal transition of cancer cells.

Epithelial–mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFβ–SMAD signaling pathway as an inductor of EMT in many tumor types is well recognized. However, the role of non-canonical TGFβ–TAK1 signaling in EMT remains unclear. Herein, we show that TAK1 deficiency drives metastatic skin squamous cell carcinoma earlier into EMT that is conditional on the elevated cellular ROS level. The expression of TAK1 is consistently reduced in invasive squamous cell carcinoma biopsies. Tumors derived from TAK1-deficient cells also exhibited pronounced invasive morphology. TAK1-deficient cancer cells adopt a more mesenchymal morphology characterized by higher number of focal adhesions, increase surface expression of integrin α5β1 and active Rac1. Notably, these mutant cells exert an increased cell traction force, an early cellular response during TGFβ1-induced EMT. The mRNA level of ZEB1 and SNAIL, transcription factors associated with mesenchymal phenotype is also upregulated in TAK1-deficient cancer cells compared with control cancer cells. We further show that TAK1 modulates Rac1 and RhoA GTPases activities via a redox-dependent downregulation of RhoA by Rac1, which involves the oxidative modification of low-molecular weight protein tyrosine phosphatase. Importantly, the treatment of TAK1-deficient cancer cells with Y27632, a selective inhibitor of Rho-associated protein kinase and antioxidant N-acetylcysteine augment and hinders EMT, respectively. Our findings suggest that a dysregulated balance in the activation of TGFβ–TAK1 and TGFβ–SMAD pathways is pivotal for TGFβ1-induced EMT. Thus, TAK1 deficiency in metastatic cancer cells increases integrin:Rac-induced ROS, which negatively regulated Rho by LMW-PTP to accelerate EMT.

Delinquency and Reputational Orientations of Adolescent At-Risk and Not-at-Risk Males and Females.

This research investigated differences in delinquent activities and the reputational orientations of at‐risk and not‐at‐risk male and female adolescents. Initially, we sought to establish that adolescent males and females differed in these respects. This was found to be the case: males (n = 722) scored significantly higher than females (n = 738) on seven self‐reported delinquency variables and on eight reputation enhancement variables pertaining to social deviance, non‐conforming reputation, and power/evaluation private identity. When a sample of 31 at‐risk females was subsequently pair‐wise age matched with 31 not‐at‐risk females, at‐risk females scored significantly higher on all delinquency variables other than school misdemeanors. These at‐risk females also scored significantly higher on four reputation enhancement variables relating to social deviance and non‐conformity. Given that at‐risk females did not differ from their not‐at‐risk counterparts in level of involvement in school misdemeanors, we sought to determine whether this was also the case for at‐risk and not‐at‐risk males. An age‐matched sample of 91 pairs revealed that at‐risk males reported significantly higher involvement than not‐at‐risk males in all aspects of delinquency, including school misdemeanors. They also sought a more non‐conforming reputation. To explore the relationships between delinquency and reputation enhancement, a canonical correlation analysis was performed. All findings are discussed in the light of reputation enhancement theory.

Treating Comorbid Anxiety in Adolescents With ADHD Using a Cognitive Behavior Therapy Program Approach

Objective: To evaluate an 8-week cognitive behavior therapy (CBT) treatment specifically designed for adolescents with ADHD and comorbid anxiety. Method: Using a multiple baseline design, nine adolescents (13 years to 16 years 9 months) received a weekly CBT, which focused on four identified anxiety-arousing times. Participants self-recorded their levels of anxiety for each of the four times during baseline, intervention, and a maintenance phase. Anxiety was also assessed using the Multidimensional Anxiety Scale for Children (MASC). Results: Paired samples t tests supported the success of the intervention. Interrupted time-series data for each participant revealed varying rates of success across the four times, however. The MASC data revealed significant reductions in Physical Symptoms of Anxiety, Social Anxiety, Separation Anxiety, Harm Avoidance, and Total Anxiety. Conclusion: The data demonstrate the efficacy of a CBT program for the treatment of comorbid anxiety in adolescents with ADHD.

Self-reported delinquency and reputational orientations of high school and incarcerated adolescent loners and nonloners

The self-reported delinquency and reputational orientations of loners and nonloners were examined in two related investigations. In the first, 1328 high school students and 132 institutionalized youth were classified as either loners or nonloners. Two multivariate analyses of variance revealed no significant main effect of loner status for delinquency, but there were main effects for gender and age. For reputational orientations, there were main effects of loner status, gender, and age. Of the 113 participants identified as loners (75 male and 38 female), 98 were age and gender matched with nonloners for further investigation. Two multivariate analyses of variance with follow-up univariates revealed a main effect of delinquency for loner status, with loners reporting higher levels of involvement in physical aggression, stealing offences, and vehicle-related offences. A significant main effect of loner status was also evident for reputational orientation. Overall, the reputational orientations of loners were suggestive of individuals who wish to be nonconforming but desire this to be of a private nature, which may be why they commit delinquent activities without the presence of an audience. These findings are discussed in the light of reputation enhancement theory.

ANGPTL4 T266M variant is associated with reduced cancer invasiveness

Angiopoietin-like 4 (ANGPTL4) is a secretory protein that can be cleaved to form an N-terminal and a C-terminal protein. Studies performed thus far have linked ANGPTL4 to several cancer-related and metabolic processes. Notably, several point mutations in the C-terminal ANGPTL4 (cANGPTL4) have been reported, although no studies have been performed that ascribed these mutations to cancer-related and metabolic processes. In this study, we compared the characteristics of tumors with and without wild-type (wt) cANGPTL4 and tumors with cANGPTL4 bearing the T266M mutation (T266M cANGPTL4). We found that T266M cANGPTL4 bound to integrin α5β1 with a reduced affinity compared to wt, leading to weaker activation of downstream signaling molecules. The mutant tumors exhibited impaired proliferation, anoikis resistance, and migratory capability and had reduced adenylate energy charge. Further investigations also revealed that cANGPTL4 regulated the expression of Glut2. These findings may explain the differences in the tumor characteristics and energy metabolism observed with the cANGPTL4 T266M mutation compared to tumors without the mutation.

Rates of Self-reported Delinquency among Western Australian Male and Female High School Students: The male–female gender gap

The Adapted Self-Report Delinquency Scale (ASDS) was administered to 328 adolescents (174 males and 154 females) from eight high schools in Perth, Western Australia. The ages of the sample ranged from 13 to 17 years. Males reported a greater percentage level of involvement than females in 36 of 40 individual delinquent behaviours comprising the ASDS. A between-subjects multivariate analysis of variance using a Bonferroni adjusted alpha revealed a significant multivariate main effect of gender, F(6, 318) = 3.98, p < 0.001, partial η 2 = 0.08. No significant main effect of age was evident. Univariate F-tests revealed that males scored significantly higher than females on only one of seven delinquent factors (physical aggression). These data are discussed in light of established evidence showing male predominance in delinquency, recent reports suggesting a male–female gender gap, and theories that have attempted to explain this disparity in offending among males and females.