PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier–penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy

Adherence to daily dietary and activity goals set within a Māori and Pacific weight loss competition.

Background: New Zealand Pacific and Māori populations measure disproportionately high on the international body mass index (BMI). Information is needed on what behavioural weight loss goals to recommend and how to attract and retain them in interventions. Our team weight loss competition trial for participants with a BMI ≥30 used cash prizes to incentivise completion of nine daily behaviour goals. This paper evaluates the theoretical merit of and adherence to these goals. Methods: A qualitative component evaluation methodology was used. Trial data on team activity, demographics and anthropometric outcome data were extracted to determine frequency of daily goal completion by teams throughout the competition and to describe participant characteristics. T-tests were used to compare completion rates of the challenges, challenge completion by day of week and between weekdays and weekends. To examine adherence to the daily challenge activity over 24 weeks the total amount of completed challenges adjusted for number of active teams was plotted by week. A Body Shape Index (ABSI) was used to determine individual anthropometric change from baseline to 8, 16 and 24 weeks. Program documents were analysed to identify barriers to adherence and retention of participants. Results: Of 19 teams (N = 130) who began only five teams performed daily goals across the whole 24 weeks. Adherence was highest during the first 8 weeks. No difference in performance between goals was found suggesting they were equally viable, though tasks worth less points were performed more frequently. Goal completion was higher on weekdays. The behaviour goals appeared to have theoretical merit in that more members of high performing teams experienced a positive change in their ABSI. Conclusions: Incentives offer a promising strategy for encouraging retention in weight loss interventions. This study suggests that participants in a competition will perform incentivised tasks. The findings however, are limited by missing data and high drop out of individuals and whole teams. Further research is needed on how to increase retention.New Zealand Ministry of Healt

Mental Health Status of Double Minority Adolescents: Findings from National Cross-Sectional Health Surveys

Little population-based work has been published about the mental health of adolescents with both sexual/gender (SG) and ethnic minority (i.e. double minority) status. This study aimed to provide an overview on their mental health. Analysis of data from a total of 17,607 high school students from New Zealand’s 2007 and 2012 cross-sectional nationally representative Adolescent Health Surveys, including a total of 1306 (7.4%) SG minority participants, of whom 581 (3.3%) were also an ethnic minority. SG minority status, minority ethnicity, and female sex were associated with higher mental distress and poorer well-being. Generally speaking, double minority students reported poorer mental health than SG majority students of the same ethnicity, but reported better mental health than SG minority New Zealand European students. Explanations and future directions for research were suggested to further explore how double minority students negotiate mental health in the context of their communities/cultures in New Zealand