Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

Summary: The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma. : Using peptide phosphorylation profiling, Zomerman et al. identify two medulloblastoma phosphoprotein-signaling profiles that have prognostic value and are potentially targetable. They find that these profiles extend across transcriptome-based subgroup borders. This suggests that diverse genetic information converges on common protein-signaling pathways and highlights protein-signaling as a unique information layer. Keywords: medulloblastoma, protein-signaling, protein synthesis, MYC, TP53, proteome, phosphoproteom

Sports Participation and Juvenile Delinquency: A Meta-Analytic Review

Participation in sports activities is very popular among adolescents, and is frequently encouraged among youth. Many psychosocial health benefits in youth are attributed to sports participation, but to what extent this positive influence holds for juvenile delinquency is still not clear on both the theoretical and empirical level. There is much controversy on whether sports participation should be perceived as a protective or a risk factor for the development of juvenile delinquency. A multilevel meta-analysis of 51 published and unpublished studies, with 48 independent samples containing 431 effect sizes and N = 132,366 adolescents, was conducted to examine the relationship between sports participation and juvenile delinquency and possible moderating factors of this association. The results showed that there is no overall significant association between sports participation and juvenile delinquency, indicating that adolescent athletes are neither more nor less delinquent than non-athletes. Some study, sample and sports characteristics significantly moderated the relationship between sports participation and juvenile delinquency. However, this moderating influence was modest. Implications for theory and practice concerning the use of sports to prevent juvenile delinquency are discussed. Keywords Sports participation Juvenile delinquency Multilevel meta-analysis Revie

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Similarities and differences between youth who engaged in intrafamilial and extrafamilial sexually abusive behavior: An exploratory study

This study examined differences between youth who engaged in intrafamilial (ISAB) and extrafamilial sexually abusive behavior (ESAB) on various characteristics covering the sociodemographic, offense-related, psychological, and environmental domains. A total of 85 Dutch male youth participated in this study. Information was obtained through self-report questionnaires and systematic screening of the case files. Youth who engaged in ISAB, compared with ESAB, came from larger families, were enrolled in higher levels of secondary education and started sexual offending at a younger age. Youth who engaged in ESAB were more frequently diagnosed with attention-deficit hyperactivity disorder (ADHD) and intellectual disabilities (ID) and primarily received longer treatment in the context of residential care. The findings are discussed in connection to the literature on (adult) sexual offending. The risk factors and criminogenic needs that distinguish youth who engaged in ISAB and ESAB appear different from those found in adult populations

External sources promoting resilience in adults with intellectual disabilities: a systematic literature review

Background: Persons with an intellectual disability are at increased risk of experiencing adversities. The current study aims at providing an overview of the research on how resilience in adults with intellectual disabilities, in the face of adversity, is supported by sources in their social network. Method: A literature review was conducted in the databases Psycinfo and Web of Science. To evaluate the quality of the included studies, the Mixed Method Appraisal Tool (MMAT) was used. Results: The themes: “positive emotions,” “network acceptance,” “sense of coherence” and “network support,” were identified as sources of resilience in the social network of the adults with intellectual disabilities. Conclusion: The current review showed that research addressing sources of resilience among persons with intellectual disabilities is scarce. In this first overview, four sources of resilience in the social network of people with intellectual disabilities were identified that interact and possibly strengthen each other

Effectiveness of Moral Developmental Interventions for Youth Engaged in Delinquent Behavior:A Meta-Analysis

There is vast empirical evidence showing that juvenile delinquency is associated with delays in moral development, including moral judgment, empathy, and self-conscious emotions (guilt and shame). Consequently, interventions have been developed that target moral development of juvenile delinquents to reduce criminal offense recidivism. However, a comprehensive synthesis of studies examining the effectiveness of these interventions was not yet available. The present meta-analysis of (quasi-)experimental research therefore examined the effects of interventions that target moral development of youth engaged in delinquent behavior. Interventions that targeted moral judgment (11 studies and 17 effect sizes) showed a significant and small-to-medium effect on moral judgment (d = 0.39), with intervention type as a significant moderator, but no significant effect on recidivism (d = 0.03; 11 studies and 40 effect sizes). No (quasi-)experimental studies were found that targeted guilt and shame in juvenile offenders, and an insufficient number of studies (i.e., only two) were found to conduct a meta-analysis of interventions that target empathy. The discussion focuses on potential ways to improve moral development interventions for youth engaged in delinquent behavior, and provides suggestions for future research.</p

Spruit_Predictors_intervention_success_AJB_Supplement – Supplemental material for Predictors of Intervention Success in a Sports-Based Program for Adolescents at Risk of Juvenile Delinquency

<p>Supplemental material, Spruit_Predictors_intervention_success_AJB_Supplement for Predictors of Intervention Success in a Sports-Based Program for Adolescents at Risk of Juvenile Delinquency by Anouk Spruit, Claudia van der Put, Eveline van Vugt, and Geert Jan Stams in International Journal of Offender Therapy and Comparative Criminology</p