IntroductionThe subventricular zone (SVZ) has been implicated in the pathogenesis of glioblastoma. Whether molecular subtypes of glioblastoma arise from unique niches of the brain relative to the SVZ remains largely unknown. Here, we tested whether these subtypes of glioblastoma occupy distinct regions of the cerebrum and examined glioblastoma localization in relation to the SVZ.MethodsPre-operative MR images from 217 glioblastoma patients from The Cancer Imaging Archive were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Probabilistic maps of tumor location were generated for each subtype and distances were calculated from the centroid of CE tumor volumes to the SVZ. Glioblastomas that arose in a Genetically Modified Murine Model (GEMM) model were also analyzed with regard to SVZ distance and molecular subtype.ResultsClassical and mesenchymal glioblastomas were more diffusely distributed and located farther from the SVZ. In contrast, proneural and neural glioblastomas were more likely to be located in closer proximity to the SVZ. Moreover, in a GFAP-CreER; PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1−/− GEMM model of glioblastoma where tumor can spontaneously arise in different regions of the cerebrum, tumors that arose near the SVZ were more likely to be of proneural subtype (p < 0.0001).ConclusionsGlioblastoma subtypes occupy different regions of the brain and vary in proximity to the SVZ. These findings harbor implications pertaining to the pathogenesis of glioblastoma subtypes.

Context Research has been scarce on health professionals’ knowledge about guidelines regulating service dogs in a clinical setting. Gaining insight into health professionals’ understanding of Americans with Disabilities Act (ADA) regulations concerning service dogs is critical for navigating compliance and reducing risk. Misinformation about service dogs could influence decisions affecting policy and care, leading to poor treatment and suboptimal health outcomes for patients with service animals. Objectives To assess health professionals’ knowledge about ADA regulations and beliefs about workplace protocols and training related to service dogs. Methods The study used snowball sampling to distribute surveys to health professionals from around the United States. Initial outreach occurred using mailing lists, investigators’ personal networks, and social media. The survey contained 24 items. True and false questions were used to test ADA knowledge and then coded as correct or incorrect. Most closed-end questions were measured on a 5-point Likert scale using frequencies and descriptive statistics. A one-way analysis of variance (ANOVA) was conducted to test whether variables, such as encounters to service dogs, affected knowledge of ADA requirements. Results The survey was completed by 441 health professionals from around the country. Most (234; 53.1%) worked in a hospital and came from a range of professional backgrounds (nurses, 155 [35.2%]; physicians, 71 [16.1%]). While nearly three-quarters (318 [73.1%]) of participants said their workplace had a policy on service animals, 113 (34.9%) of those said they were unfamiliar with the policy and 236 (54.5%) said they had not received adequate training on the topic. Most participants did not know basic ADA policy requirements related to service dogs. Only those who were extremely familiar with policy (F=4.613; p=0.001) and those who strongly agreed that they knew the differences between service dogs and other classes of animals (F=5.906; p=0.000) scored higher on the knowledge test than those who disagreed. Conclusions Our results suggest that increased familiarity and training leads to higher knowledge about service dogs and ADA policy. Health professionals need additional education on ADA service dog regulations and hospital policy in order to minimize risk and ensure patients with service dogs receive optimal care.

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Platelet-derived growth factor (PDGF) signaling plays a key role in gliomagenesis. Glioblastomas express all PDGF ligands, and both cell membrane receptors, PDGFRα and PDGFRβ, that are involved in pro-survival autocrine and paracrine loops. Our previous work demonstrated that expression of PDGFRb is enriched in hypoxic glioblastoma tumor tissues. Also, induction of mitophagy is a well-known critical coping response to tissue hypoxia. We therefore investigated the role of PDGFRb signaling cascade in regulating hypoxia-induced mitophagy of glioblastoma. PDGFRb signaling was essential for induction of hypoxiamediated mitophagy in glioblastoma cells. METHODS & RESULTS: Western blotting and immunofluorescence imaging with either RNA interference of PDGFRb or treatment with PDGFRb inhibitor showed that NIX, a hypoxic responsive protein and regulator of mitophagy, was necessary for PDGFRb-mediated glioblastoma survival under hypoxia. Detecting MitoSOX and MitoTracker Green along with treatment of PDGFRb inhibitor suggested that inhibition of PDGFRb signaling pathway led to accumulation of mitochondrial ROS, and subsequently killing glioblastoma cells by suppressing mitophagy. In tumor bearing mice model, PDGFRb inhibitor attenuated growth of tumor mass, however, ectopic NIX expression reversed such effect. Furthermore, interference of mitophagic response by blocking PDGFRβ signaling enhanced cell death even in temozolomideresistant tumor cells. CONCLUSIONS: This work suggests a potential mechanism by which PDGFRb inhibition could kill glioblastoma cells through suppression of NIX-mediated mitophagy. Manipulation of NIX and PDGFRb pathway may provide novel therapeutic opportunities in chemoresistant tumor models.

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