24 research outputs found

    ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

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    Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992

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

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    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.

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    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

    Museums Brand Equity and Social Media: Looking into Current Research Insights and Future Research Propositions

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    Abstract. Extensive research has repeatedly acknowledged the link between traditional and digital marketing communication tools and branding performance. Particularly, both within For Profit Organizations (henceforth, FPOs) and Non-Profit Organizations (henceforth NPOs), social media as the milestone of the digital era has rebutted the foundations of corporate and personal communication through the emergence of new participatory communication terms, such as ''prod-user'' and “co-creation”. Consequently, a growing research trend has emerged towards e-e marketing tools and social media impact on destination branding, as well. Simultaneously, thanks to its multidimensional benefits both at the communicational, educational, and promotional levels, social media are emerging as an essential feature in the branding of the new museum era. To date, within the NPOs sector, few studies have investigated the effect of social media on brand equity. Moreover, far too little attention has been paid to the link between social media and museums' brand equity. Based on the systematic qualitative critical review methodology, this paper attempts to identify the basic trends and research status by 2018. Drawing on a review of 78 papers that are the result of systematic desk research, this study categorizes and presents, for the first time, the effects of social media use on museums’ brand components. The study offers new and valuable insights into the multidisciplinary research interests of the research and industry community relating to communication and marketing, NPOs, tourism, and museums context. Keywords: Social Media, Museums, Brand Equity, NPOs, Cultural Tourism

    Investigation of damage: Brisbane 27 November 2014 severe storm event

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    Between 2 and 6 pm the on the 27th of November 2014 severe thunderstorm activity was observed in the South-East Queensland region. Two adjoining storm cells moving in a northerly direction subjected Brisbane and neighbouring suburbs to severe hail, damaging winds and localized flooding. A maximum gust wind speed of 141 km/h was measured at Archerfield Airport during this event. However, from wind field analyses and field observations, speeds were estimated to be approximately 40 to 80 km/h in other affected suburbs. Severe hail accompanied the storm (40 mm diameter typical), with hail damage to windows being widespread. Street and house surveys were conducted between the 28th of November and the 5th of December to assess structural damage and to compare overall impacts of the storm to what was reported by journalists and social media. An analysis of damage severity in relation to construction materials was then performed allowing patterns of housing stock vulnerabilities to be examined. Hail damage to windows and subsequent water ingress was particularly high, especially for older housing, with older window glass performing poorly against the wind-driven hail compared to newer window glass. Another contributing factor was most likely the significant horizontal component in the trajectory of the hail caused by the strong winds. Although winds were lower than design level, some cases of severe roof failures did occur. On several occasions, these failures were due to: (i) building age with rot in timber roof members and/or corrosion of connections or (ii) installation of new roof cladding without upgrading the batten to rafter or rafter to wall tie down connections to contemporary building standards. Roof structure damage was typically associated with a breach in the windward wall allowing a large increase in internal pressure and adding to the external suction loads on the roof.\u
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