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

Multiscale multifactorial approaches for engineering tendon substitutes

The physiology of tendons and the continuous strains experienced daily make tendons very prone to injury. Excessive and prolonged loading forces and aging also contribute to the onset and progression of tendon injuries, and conventional treatments have limited efficacy in restoring tendon biomechanics. Tissue engineering and regenerative medicine (TERM) approaches hold the promise to provide therapeutic solutions for injured or damaged tendons despite the challenging cues of tendon niche and the lack of tendon-specific factors to guide cellular responses and tackle regeneration. The roots of engineering tendon substitutes lay in multifactorial approaches from adequate stem cells sources and environmental stimuli to the construction of multiscale 3D scaffolding systems. To achieve such advanced tendon substitutes, incremental strategies have been pursued to more closely recreate the native tendon requirements providing structural as well as physical and chemical cues combined with biochemical and mechanical stimuli to instruct cell behavior in 3D architectures, pursuing mechanically competent constructs with adequate maturation before implantation.Authors acknowledge the project “Accelerating tissue engineering and personalized medicine discoveries by the integration of key enabling nanotechnologies, marinederived biomaterials and stem cells,” supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Authors acknowledge the H2020 Achilles Twinning Project No. 810850, and also the European Research Council CoG MagTendon No. 772817, and the FCT Project MagTT PTDC/CTM-CTM/ 29930/2017 (POCI-01-0145-FEDER-29930

Variations of near-surface firn density in the lower accumulation area of the Greenland ice sheet, Pakitsoq, West Greenland

AbstractFirn-density variations have been studied in the lower accumulation area of the Greenland ice sheet (1440-1620 m a.s.l.) near Pâkitsoq, West Greenland. The main control on density in the near-surface firn layer (of 5-10 m thickness) is the formation of ice layers by the refreezing of meltwater that reaches depths of 2-4 m below the surface. The density variations are described by the ratio of annual surface meltMto the annual accumulationC. The ratioM/Cis about 0.6 at the run-off limit (at about 1400 m a.s.l. in the study area) where refreezing of meltwater transforms snow into impermeable ice. The mean density of near-surface firn decreases with elevation, reflecting a decrease in melt with elevation. There is a surprising decrease in firn density at depths of more than about 4 m below the 1991 summer surface, which reflects lower melt rates and/or higher accumulation in the early 1980s and late 1970s when this firn was passing through the surface layer. The formation of such low-density firn may have partially contributed to the 1978-85 thickening of the ice sheet observed by satellite-radar altimetry. Near-surface firn density is therefore very sensitive to climate change and might be an attractive target for climate monitoring.</jats:p