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Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and classical subtypes, and have raised expectations these insights may predict response to targeted therapies. We utilized GBM neurospheres that display GSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. The PI3Kα selective inhibitor alpelisib blocked PI3K/AKT activation and inhibited spheroid growth, suggesting an essential role for the PI3Kα catalytic isoform. p110α expression was highest in the proneural subtype and this was associated with increased phosphorylation of AKT. Further, employing the GBM BioDP, we found co-expression of PIK3CA with the neuronal stem/progenitor marker NES was associated with poor prognosis in PN GBM patients, indicating a unique role for PI3Kα in PN GSCs. Alpelisib inhibited GSC neurosphere growth and these effects were more pronounced in GSCs of the PN subtype. The antineoplastic effects of alpelisib were substantially enhanced when combined with pharmacologic mTOR inhibition. These findings identify the alpha catalytic PI3K isoform as a unique therapeutic target in proneural GBM and suggest that pharmacological mTOR inhibition may sensitize GSCs to selective PI3Kα inhibition.

Medulloblastoma is the most common paediatric malignant brain cancer and there is a need for new targeted therapeutic approaches to more effectively treat these malignant tumours, which can be divided into four molecular subtypes. Here, we focus on targeting sonic hedgehog (SHH) subtype medulloblastoma, which accounts for approximately 25% of all cases. The SHH subtype relies upon cholesterol signalling for tumour growth and maintenance of tumour-initiating cancer stem cells (CSCs). To target cholesterol signalling, we employed biomimetic high-density lipoprotein nanoparticles (HDL NPs) which bind to the HDL receptor, scavenger receptor type B-1 (SCARB1), depriving cells of natural HDL and their cholesterol cargo. We demonstrate uptake of HDL NPs in SCARB1 expressing medulloblastoma cells and depletion of cholesterol levels in cancer cells. HDL NPs potently blocked proliferation of medulloblastoma cells, as well as hedgehog-driven Ewing sarcoma cells. Furthermore, HDL NPs disrupted colony formation in medulloblastoma and depleted CSC populations in medulloblastoma and Ewing sarcoma. Altogether, our findings provide proof of principle for the development of a novel targeted approach for the treatment of medulloblastoma using HDL NPs. These findings present HDL-mimetic nanoparticles as a promising therapy for sonic hedgehog (SHH) subtype medulloblastoma and possibly other hedgehog-driven cancers.

Background Glioblastoma (GBM) cellularity correlates with whole brain spectroscopic MRI (sMRI) generated relative choline to N -Acetyl-Aspartate ratio (rChoNAA) mapping. In recurrent GBM (rGBM), tumor volume (TV) delineation is challenging and rChoNAA maps may assist with re-RT targeting. Methods Fourteen rGBM patients underwent sMRI in a prospective study. Whole brain sMRI was performed to generate rChoNAA maps. TVs were delineated by the union of rChoNAA ratio over 2 (rChoNAA > 2) on sMRI and T1PC. rChoNAA > 2 volumes were compared with multiparametric MRI sequences including T1PC, T2/FLAIR, diffusion-restriction on apparent diffusion coefficient (ADC) maps, and perfusion relative cerebral blood volume (rCBV). Results rChoNAA > 2 (mean 27.6 cc, range 6.6–79.1 cc) was different from other imaging modalities ( P  ≤ 0.05). Mean T1PC volumes were 10.7 cc (range 1.2–31.4 cc). The mean non-overlapping volume of rChoNAA > 2 and T1PC was 29.2 cm 3 . rChoNAA > 2 was 287% larger (range 23% smaller–873% larger) than T1PC. T2/FLAIR volumes (mean 111.7 cc, range 19.0–232.7 cc) were much larger than other modalities. rCBV volumes (mean 6.2 cc, range 0.2–19.1 cc) and ADC volumes were tiny (mean 0.8 cc, range 0–3.7 cc). Eight in-field failures were observed. Three patients failed outside T1PC but within rChoNAA > 2. No grade 3 toxicities attributable to re-RT were observed. Median progression-free and overall survival for re-RT patients were 6.5 and 7.1 months, respectively. Conclusions Treatment of rGBM may be optimized by sMRI, and failure patterns suggest benefit for dose-escalation within sMRI-delineated volumes. Dose-escalation and radiologic-pathologic studies are underway to confirm the utility of sMRI in rGBM.

Background Outcomes in glioblastoma are improved by surgical resection and adjuvant radiation (RT). In primary GBM (pGBM), large clinical target volume (CTV) margins typically cover occult invasion. In recurrent GBM (rGBM), RT often uses tiny CTV margins that likely omit occult invasion due to re-RT radiation necrosis concerns. Whole-brain spectroscopic MRI (sMRI) is an emerging technique with similar resolution to PET that may help define the CTV for rGBM. Methods Patients with pGBM ( n  = 18) and rGBM ( n  = 19) underwent sMRI with RT simulation. T1-post contrast (T1PC) and T2/FLAIR MRI volumes were contoured. sMRI generated choline/N-acetylaspartate > 2x (Cho/NAA > 2x) volumes are known to correlate with high-risk invasion. Hausdorff distances were calculated to define the margin necessary to cover Cho/NAA > 2x in pGBM and rGBM. In rGBM, mock CTV expansions from T1PC volumes were created to determine non-selective CTV expansion sizes needed to cover Cho/NAA > 2x volumes. Results For pGBM, the median T1PC, Cho/NAA > 2x, and T2/FLAIR volumes were 32.3 cc, 45.0 cc, and 74.8 cc respectively. For rGBM, the median T1PC, Cho/NAA > 2x, and T2/FLAIR volumes were 21.7 cc, 58.9 cc, and 118.3 cc, respectively. T2/FLAIR volumes increased more relative to T1PC volumes in rGBM than pGBM ( p  ≤ 0.001). Meanwhile, the median Hausdorff distance between T1PC and Cho/NAA > 2x was 22.9 mm in pGBM and 25.7 mm in rGBM, suggesting that the high-risk volume does not significantly change. In rGBM, it is common to use no CTV expansion from the T1PC volume which only included 61% of high-risk Cho/NAA > 2x volume. Conversely, T1PC expansions of 10-, 15-, and 20-mm covered 87%, 94%, and 98% of Cho/NAA > 2x volume. Conclusions sMRI Cho/NAA > 2x delineates high-risk occult disease in glioblastoma and extends beyond T1PC MRI borders. Typical large CTV expansions in pGBM mostly include Cho/NAA > 2x volumes. However, small CTV expansions commonly used in rGBM poorly cover Cho/NAA > 2x, suggesting that larger CTV expansions or Cho/NAA > 2x guidance may be of benefit.

Despite recent advances in the treatment of medulloblastoma, patients in high-risk categories still face very poor outcomes. Evidence indicates that a subpopulation of cancer stem cells contributes to therapy resistance and tumour relapse in these patients. To prevent resistance and relapse, the development of treatment strategies tailored to target subgroup specific signalling circuits in high-risk medulloblastomas might be similarly important as targeting the cancer stem cell population. We have previously demonstrated potent antineoplastic effects for the PI3Kα selective inhibitor alpelisib in medulloblastoma. Here, we performed studies aimed to enhance the anti-medulloblastoma effects of alpelisib by simultaneous catalytic targeting of the mTOR kinase. Pharmacological mTOR inhibition potently enhanced the suppressive effects of alpelisib on cancer cell proliferation, colony formation and apoptosis and additionally blocked sphere-forming ability of medulloblastoma stem-like cancer cells in vitro . We identified the HH effector GLI1 as a target for dual PI3Kα and mTOR inhibition in SHH-type medulloblastoma and confirmed these results in HH-driven Ewing sarcoma cells. Importantly, pharmacologic mTOR inhibition greatly enhanced the inhibitory effects of alpelisib on medulloblastoma tumour growth in vivo . In summary, these findings highlight a key role for PI3K/mTOR signalling in GLI1 regulation in HH-driven cancers and suggest that combined PI3Kα/mTOR inhibition may be particularly interesting for the development of effective treatment strategies in high-risk medulloblastomas.

Patients with head and neck malignancies commonly develop metastatic disease, yet rarely do these carcinomas metastasize to the brain. Stereotactic radiosurgery (SRS) is routinely employed to treat brain metastases (BM). This study was undertaken to examine the efficacy of SRS for BM from primary head and neck carcinomas. From 2000 to 2016, a total of 19 patients with 38 lesions were retrospectively identified. All patients presented with a primary head and neck malignancy and subsequently developed metastatic disease to the brain treated with SRS at our institution. Actuarial rates for overall survival (OS), local control (LC) and distant brain metastases (DBM) were calculated using Kaplan–Meier estimates. Median follow up was 6.8 months and median survival was 15.8 months. Eleven lesions received post-operative SRS to a surgical cavity and 27 lesions received definitive SRS to a metastasis. The median dose prescribed was 18 Gy. One-year actuarial rate for LC was 77.3% (95% confidence interval [CI] 44–92%) while 1 year and 2 year rates of OS were 52.9% (CI 28–73%) and 31.7% (CI 11–55%) respectively. The median time to develop DBM was 8.4 months. Three patients (16%) underwent repeat SRS following development of new BM and three patients (16%) underwent salvage whole brain radiotherapy (WBRT). SRS may be utilized in the treatment of patients with primary head and neck malignancies metastasized to the brain with high efficacy. Patients with well-controlled systemic disease and good performance status may benefit the most from definitive SRS while avoiding WBRT.

The Department of Defense (DOD) and the US Government face a significant national security challenge in adversarial use of small unmanned aircraft systems (sUAS). The available technology to create swarms of these capabilities results in multilayered and unmanageable threats. Here, Bell addresses ways to prepare for and respond to this looming challenge, colloquially known as \"drone swarms.\" Driving this concern are underlying questions that challenge conventional thinking and practice. Some of the unanswered issues include the potential capability of sUAS swarms against US interests and the reciprocal response.

Key Points Single-celled eukaryotes (protists) constitute a tremendously diverse group of microorganisms. These species exhibit a wide range of nutritional modes (many species possess multiple nutritional modes simultaneously) and are essential components at several trophic levels within food webs. Genetic analyses of protists have lagged behind those of other microbial taxa because protists have much larger genomes and more complicated gene expression patterns. Consequently, we have very limited knowledge about gene number, identity and function within many protistan lineages. Widespread application of targeted gene sequencing (most notably, of small-subunit rRNA genes) has greatly improved our knowledge of eukaryote phylogeny and provided a framework for an emerging taxonomy incorporating morphological and molecular information. A recently developed alternative approach to provide genetic information for ecologically important protistan taxa is transcriptome sequencing of cultured species. Transcriptomes are providing vital databases of genes for species that lack sequenced genomes. Transcriptomic studies of cultures and natural assemblages of phototrophic protists (phytoplankton) are revealing complex metabolic responses to environmental conditions (such as nutrient limitation and light regime), pathways that are involved in toxin production by some harmful algal species and changes in gene expression that are related to shifts in nutritional mode for mixotrophic species. The application of transcriptomic approaches to the study of protistan symbioses, predator–prey interactions and protist–bacterium interactions are beginning to reveal the molecular signalling that is involved in the recognition and response between microorganisms, providing insights into the origin of eukaryotic organelles and the structure of aquatic food webs. We now have an improved understanding of the physiological responses of ecologically relevant protistan species and trophic groups to environmental changes. This understanding, which has been garnered through omics studies, is being harnessed to improve the predictive capabilities of global biogeochemical models. Protists are an important part of the marine food web. In this Review, Caron et al . summarize recent insights from transcriptomic studies of cultured and free-living protists and discuss how these findings highlight the functions and interactions of these single-celled eukaryotes in the global oceans. Protists, which are single-celled eukaryotes, critically influence the ecology and chemistry of marine ecosystems, but genome-based studies of these organisms have lagged behind those of other microorganisms. However, recent transcriptomic studies of cultured species, complemented by meta-omics analyses of natural communities, have increased the amount of genetic information available for poorly represented branches on the tree of eukaryotic life. This information is providing insights into the adaptations and interactions between protists and other microorganisms and macroorganisms, but many of the genes sequenced show no similarity to sequences currently available in public databases. A better understanding of these newly discovered genes will lead to a deeper appreciation of the functional diversity and metabolic processes in the ocean. In this Review, we summarize recent developments in our understanding of the ecology, physiology and evolution of protists, derived from transcriptomic studies of cultured strains and natural communities, and discuss how these novel large-scale genetic datasets will be used in the future.