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Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.

While quantitative approaches cannot replace disciplinary insights from the social sciences and humanities, they can sometimes provide new perspectives. Building upon research from psychology and organizational theory that demonstrates how interacting groups may benefit both from diversity and from shared identity, we present a mathematical framework to explore the interplay of these collective attributes. We define intersecting diversity to capture the distribution of multidimensional identity traits and shared identity to describe the extent to which traits are shared amongst individuals. Although these two quantities are theoretically independent, we find a strong negative correlation between them in two sample data sets: principal creative contributors to Hollywood box office movies and American Community Survey data on state populations. This apparent trade-off between group diversity and shared identity poses a dilemma as both attributes are beneficial for group functioning.

Online education is a rapidly growing segment of the postsecondary system, and recent growth is concentrated at non-profit universities. Research shows that Black and low-income students are disproportionately represented in online programs; however, research on the outcomes of exclusively online education, especially at four-year non-profit universities, has been limited. Two narratives have emerged about the consequences of the access that online education provides: one describing it as promising and the other describing it as predatory. We harness both institution-level data and individual-level data to intervene in this debate. We show that online education is related to worse educational outcomes in non-profit and for-profit sectors, including lower retention and graduation rates. A sensitivity analysis suggests that selection into online education is unlikely to explain these results. Attending online is also related to some less desirable student loan repayment outcomes across sectors. Our results suggest that online education is a form of “predatory inclusion,” in that access is coupled with increased risks for students relative to comparable peers attending in-person. In light of our findings, we propose that the provision of online education by for-profit entities—even in the non-profit sector—may play a central role in producing poor student outcomes.

Suplemental Figure Legends for supplemental data

Supplemental Figure 1: Related to Figure 1: Characterization of Gene-Trapped Clones Supplemental Figure 2 Related to Figure 2: PINK1 alters normal astrocyte metabolism Supplemental Figure 3 Related to Figure 2: PINK1 alters normal astrocyte metabolism Supplemental Figure 4: Related to Figure 3: PINK1 alters normal astrocyte metabolism and stabilizes HIF1a Supplemental Figure 5: Related to Figure 3: PINK1 overexpression stops GBM cell growth and inhibits glycolysis. Supplemental Figure 6: Related to Figure 3: PINK1 overexpression inhibits glycolysis. Supplemental Figure 7: Related to Figure 3: PINK1 overexpression inhibits glycolysis. Supplemental Figure 8: Related to Figure 4: Selective targeting in PINK1 expressing GBM cells leads to reduced viability Supplemental Figure 9: Related to Figure 4: Targeting of PINK1 in GBM cells leads to reduced colony formation and caspase activity Supplemental Figure 10: Related to Figure 5 and 6. PINK1 expression in vivo. Supplemental Table 1: Genes identified from gene-trap screen.

Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila. Cancer Res; 76(16); 4708–19. ©2016 AACR.

Suplemental methods for experiments appearing in supplemental data and expanded details from methods in main manuscript.

Supplementary Figure S5. PDGFRÃ? pathway inhibition in foretinib treated Daoy and D425 medulloblastoma cells

Supplementary Table S1. Foretinib concentrations in mouse brain, mouse plasma and the brain-plasma ratio

Supplementary Figures 1-5 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

Medulloblastoma (MB) is a malignant cerebellar tumor that occurs primarily in children. The hepatocyte growth factor (HGF)/MET pathway has an established role in both normal cerebellar development as well as the development and progression of human brain tumors, including MB. To identify novel tumor suppressor genes involved in MB pathogenesis, we performed an epigenome-wide screen in MB cell lines, using 5-aza-2′deoxycytidine to identify genes aberrantly silenced by promoter hypermethylation. Using this technique, we identified an inhibitor of HGF/MET signaling, serine protease inhibitor kunitz-type 2 (SPINT2/HAI-2), as a putative tumor suppressor silenced by promoter methylation in MB. In addition, based on single nucleotide polymorphism array analysis in primary MB samples, we identified hemizygous deletions targeting the SPINT2 locus in addition to gains on chromosome 7 encompassing the HGF and MET loci. SPINT2 gene expression was down-regulated and MET expression was up-regulated in 73.2% and 45.5% of tumors, respectively, by quantitative real-time PCR. SPINT2 promoter methylation was detected in 34.3% of primary MBs examined by methylation-specific PCR. SPINT2 reexpression in MB cell lines reduced proliferative capacity, anchorage independent growth, cell motility in vitro, and increased overall survival times in vivo in a xenograft model (P < 0.0001). Taken together, these data support the role of SPINT2 as a putative tumor suppressor gene in MB, and further implicate dysregulation of the HGF/MET signaling pathway in the pathogenesis of MB. [Cancer Res 2008;68(23):9945–53]

Supplementary Methods and Figure Legends

Supplementary Figure 7 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

Supplementary Figure 6 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targetsEGFR-mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant,EGFR-mutant NSCLC cells.

In 2015, Wisconsin began mandating the ACT college entrance exam and the WorkKeys career readiness assessment. With population-level data and several quasi-experimental designs, we assess how this policy affected college attendance. We estimate a positive policy effect for middle/high-income students, no effect for low-income students, and greater effects at high schools that had lower ACT participation before the policy. We further find little evidence that being deemed college-ready by one’s ACT scores or career-ready by one’s WorkKeys scores affects college attendance probabilities. Pragmatically, the findings highlight the policy’s excellence and equity consequences, which are complex given that the policy has principally helped advantaged students. Theoretically, the findings shed light on students’ (dis)inclinations to update educational beliefs in light of new signals.

Racialized tracking is central to sociological explanations for racially stratified educational outcomes. However, school officials’ decision-making is of debated importance for explaining racialized tracking. We contribute to this literature by examining the effects of schools’ enrollment policies for Advanced Placement (AP) courses. Using a unique combination of school survey data and administrative data from Wisconsin, we examine what happens to racial inequality in AP participation when school officials enforce performance-based selection criteria, which we call “course gatekeeping.” We find that course gatekeeping has racially disproportionate effects. Although racialized differences in prior achievement partially explain the especially large negative effects among students of color, course gatekeeping producesBlack-white and Hispanic-white disparities in participation even among students with similar, relatively low prior achievement. We further find that course gatekeeping has longer-run effects, particularly discouraging Black and Asian or Pacific Islander students from attending highly selective four-year colleges.

For decades, cell biologists and cancer researchers have taken advantage of non-murine species to increase our understanding of the molecular processes that drive normal cell and tissue development, and when perturbed, cause cancer. The advent of whole-genome sequencing has revealed the high genetic homology of these organisms to humans. Seminal studies in non-murine organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio identified many of the signaling pathways involved in cancer. Studies in these organisms offer distinct advantages over mammalian cell or murine systems. Compared to murine models, these three species have shorter lifespans, are less resource intense, and are amenable to high-throughput drug and RNA interference screening to test a myriad of promising drugs against novel targets. In this review, we introduce species-specific breeding strategies, highlight the advantages of modeling brain tumors in each non-mammalian species, and underscore the successes attributed to scientific investigation using these models. We conclude with an optimistic proposal that discoveries in the fields of cancer research, and in particular neuro-oncology, may be expedited using these powerful screening tools and strategies.

Recent work has broadened the scope of school effectiveness research to consider not only academic achievement but also other outcomes, especially college attendance. This literature has argued that high schools are an important determinant of college attendance, with some contending that high schools matter more for college attendance than for academic achievement. A separate branch of research has illustrated how place-based opportunities facilitate college attendance. We merge these two literatures by asking if schools’ geographic context can explain apparent variation in effectiveness among Wisconsin high schools. We find that geographic context explains nearly a third of the variance in traditional estimates of school effectiveness on college attendance, because factors like proximity to colleges are strongly associated with college attendance. Accounting for geography is therefore important in order not to overstate high schools’ role in higher education outcomes. In contrast, geographic context explains little of the variance in academic achievement growth. Thus, if high schools seem to matter more for college attendance than for academic achievement under traditional estimates, schools’ apparent importance for the two outcomes converge upon adjusting for differences in geographic context. Results are based on multilevel models applied to rich administrative data on every Wisconsin public high school entrant between 2006 and 2011.

Terrorism is a major problem worldwide, causing thousands of fatalities and billions of dollars in damage every year. Toward the end of better understanding and mitigating these attacks, we present a set of machine learning models that learn from localized news data in order to predict whether a terrorist attack will occur on a given calendar date and in a given state. The best model--a Random Forest that learns from a novel variable-length moving average representation of the feature space--achieves area under the receiver operating characteristic scores $> .667$ on four of the five states that were impacted most by terrorism between 2015 and 2018. Our key findings include that modeling terrorism as a set of independent events, rather than as a continuous process, is a fruitful approach--especially when the events are sparse and dissimilar. Additionally, our results highlight the need for localized models that account for differences between locations. From a machine learning perspective, we found that the Random Forest model outperformed several deep models on our multimodal, noisy, and imbalanced data set, thus demonstrating the efficacy of our novel feature representation method in such a context. We also show that its predictions are relatively robust to time gaps between attacks and observed characteristics of the attacks. Finally, we analyze factors that limit model performance, which include a noisy feature space and small amount of available data. These contributions provide an important foundation for the use of machine learning in efforts against terrorism in the United States and beyond.

In Norway, onomastic fieldwork and the study of place names have a tradition back to the 19th c. In 20th c. numerous field work campaigns were undertaken and extensive collections were created. The last large project ended almost 40 years ago. This fact and the Norwegian ratification of the UNESCO charter for the protection of intangible cultural heritage in 2007, prompted the Norwegian Cultural Ministry to launch a funding scheme for the collection of local place names. The paper discusses the context for this decision. A digital registration system was ready in 2016 and in the same year, the first projects were funded. In the paper, the registered data are analysed and the experiences with the system are discussed. The database currently contains 126 000 detailed registrations. This is a substantial number, and the project can be considered a success. On the other hand, the number could have been higher. A reason for this is the lack of a good and user-friendly search interface and a nationwide organization taking care of datasets from onomastic fieldwork.

Substantial race-based disparities exist in federal criminal sentencing. We analyze 380,000 recent (2006-2019) sentences in the JUSTFAIR database and show that these disparities are large and vary considerably across judges. Judges assign white defendants sentences 13% shorter than Black defendants’ and 19% shorter than Hispanic defendants’, on average, conditional on case characteristics and district. Judges one standard deviation above average in their estimated Black-white disparity give Black defendants sentences 39% conditionally longer than white defendants’, vis-à-vis an average disparity of 13%. Judges one standard deviation above average in their estimated Hispanic-white disparity give Hispanic defendants sentences 49% conditionally longer than white defendants’, compared to the average disparity of 19%.

Bolstering low-income students’ postsecondary participation is important to remediate these students’ disadvantages and to improve society’s overall level of education. Recent research has demonstrated that secondary schools vary considerably in their tendencies to send students to postsecondary education, but existing research has not systematically identified the school characteristics that explain this variation. Identifying these characteristics can help improve low-income students’ postsecondary outcomes. We identify relevant characteristics using population-level data from Wisconsin, a mid-size state in the United States. We first show that Wisconsin’s income-based disparities in postsecondary participation are wide, even net of academic achievement. Next, we show that several geographic characteristics of schools help explain between-secondary school variation in low-income students’ postsecondary outcomes. Finally, we test whether a dense set of school organisational features explain any remaining variation. We find that these features explain virtually no variation in secondary schools’ tendencies to send low-income students to postsecondary education.

Public wildlife management in the United States is transforming as agencies seek relevancy to broader constituencies. State agencies in the United States, while tasked with conserving wildlife for all beneficiaries of the wildlife trust, have tended to manage for a limited range of benefits in part due to a narrow funding model heavily dependent on hunting, fishing, and trapping license buyers. To best meet the needs, interests, and concerns of a broader suite of beneficiaries, agencies will need to reconsider how priorities for management are set. This presents an opportunity for conservation program design and evaluation to be elevated in importance. We argue that success in wildlife conservation in the U.S. requires assessment of both decision-making processes and management results in relation to four questions: conservation of what, under what authority, for what purposes, and for whom?

Studying 380,000 criminal cases in federal district courts from 2006 to 2019, we replicate previous findings that aggregate, conditional racial disparities in sentence lengths are large. We further show that estimated racial disparities in sentencing vary considerably across judges. Results suggest that judges assign white defendants sentences that are conditionally 13% shorter than Black defendants’ and 19% shorter than Hispanic defendants’, on average. A judge who is one standard deviation above average in terms of estimated Black-white disparity gives Black defendants sentences that are conditionally 39% longer than white defendants’, compared to the average disparity of 13%. A judge who is one standard deviation above average in terms of estimated Hispanic-white disparity gives Hispanic defendants sentences that are conditionally 49% longer than white defendants’, compared to the average disparity of 19%.

The five most common species of Pacific salmon, Rainbow Trout (steelhead) Oncorhynchus spp., and Atlantic Salmon Salmo salar intermingle in the North Pacific Ocean and its freshwater tributaries. Efficient morphological methods for distinguishing among these species are sometimes limited by condition of the specimen (degraded or missing morphology), life history stage, or training of the observer. Researchers have successfully applied various genetic methods to distinguish among these species when morphological analyses are not possible, but they cannot easily incorporate these methods into standard fish and wildlife population monitoring analysis workflows. Here we test five 5′–3′ exonuclease (TaqMan) assays developed from mitochondrial genes and provide novel methods that take advantage of TaqMan output to distinguish among these species. We found that combinations of as few as two of the five assays were adequate to distinguish all species. TaqMan chemistry is designed to interrogate a single nucleotide locus. We also explore the basis for the variation in the observed scatter plot distributions (variation in florescent signals) and show that this variation is due to nucleotide diversity in and near the probe site. Because the SNPs underlying the assays developed here are all physically close to one another along the mitochondrial genome, the potential exists to develop a single DNA sequence-based assay to discriminate among salmon species. This single assay can be added to a genotyping-by-sequencing panel to identify and exclude nontarget species from analyses.

Knowledge of the distribution of genetic resources within and among taxa is prerequisite for development of management strategies which facilitate conservation of those resources. We used restriction-site associated DNA (RAD) sequencing to survey genetic variation in Alvord Chub and Borax Lake Chub from the Alvord Basin in southeastern Oregon and northern Nevada, USA. Our specific goals were to gain an understanding of the population genetic structure of Alvord Chub and the relationship between this species and Borax Lake Chub. Despite the fact that our collections were taken from ponds and streams, isolated from one another by kilometers of desert, our results revealed that diversity in Alvord Chub was primarily distributed among two regional groupings, which we hypothesize to be related to habitat changes following the end of the most recent glaciation event, approximately 10 thousand years ago. Our results further revealed that Alvord Chub and Borax Lake Chub shared common ancestors during that glaciation event, and that divergence between the two may have been sympatric. Finally, we observed evidence that the clade containing Alvord Chub and Borax Lake Chub was isolated from its closest extant relative, the Tui chub, during the Miocene Epoch, when volcanic flows were forming the mountains surrounding what became the Alvord Basin. These results will be useful for informing conservation strategies for Alvord Chub, and provide new insights regarding the role of these species in the evolutionary legacy of the region.

Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma. Epicranial grafting of clival chordoma collected during surgery was performed. Tumor growth was established in a nonobese diabetic/severe combined immunodeficiency mouse and tumors have been passaged serially for seven generations. Physaliferous cell architecture was shown in the regenerated tumors, which stained positive for Brachyury, cytokeratin, and S100 protein. The tumors showed bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared with the parental tumor. Copy number gain of the T gene (brachyury) and heterozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) was observed. Heterozygous loss of the tumor-suppressor fragile histidine triad (FHIT) gene also was observed, although protein expression was preserved. Accumulation of copy number losses and gains as well as increased growth rate was observed over three generations. The patient-derived xenograft reproduces the phenotype of clival chordoma. This model can be used in the future to study chordoma biology and to assess novel treatments.

Leiomyosarcoma is a common sarcoma of both organs and soft tissues; however, large intradermal tumors are extremely rare. Presented is a pleomorphic leiomyosarcoma in a 64-year-old man, initially considered to be a ruptured epidermal inclusion cyst. The patient had a mildly tender, enlarging soft-tissue mass with a central pore on his right upper back. Incomplete extirpation showed a 5 × 5 cm heterogeneous, predominantly pleomorphic sarcoma with areas of fascicular and storiform spindled cells infiltrating the subcutaneous soft tissue to the underlying fascia and extending upward into the middle and upper dermis with prominent extension into pilosebaceous units. There were small foci with myxoid stroma and large areas of necrosis. CD31 demonstrated thin-walled curvilinear vessels throughout the tumor. The first desmin immunohistochemical stain near areas with myxoid stroma was negative but smooth muscle actin positive. However, desmin positivity was strong and diffuse in the spindled and more pleomorphic areas on 2 additional tissue sections. No rhabdomyoblasts or striated muscle fibers were seen. A diagnosis of pleomorphic leiomyosarcoma was rendered. This case highlights a unique clinical and histological presentation of a leiomyosarcoma initially mistaken to be a ruptured epidermal inclusion cyst, and the need to sometimes apply ancillary immunohistochemical studies to sections from more than one tissue block to accurately differentiate heterogeneous sarcomas with similar histologic features.

Background Osteoporosis is often undiagnosed until patients experience fragility fractures. Pelvic fractures are common but underappreciated sentinel fractures. Screening patients with a pelvic fracture for osteoporosis may provide an opportunity to initiate appropriate treatments such as anti-osteoporosis therapy to prevent additional fractures. Methods This retrospective cohort review examined the management of osteoporosis after pelvic fractures at a large tertiary care center without an established secondary fracture prevention program. Data were extracted from electronic medical records of all new patients with a pelvic fracture who were ≥50 years of age from this center and its affiliated community hospitals from 2008 to 2014. Outcome measures included the initiation of anti-osteoporosis therapy before the fracture, within the year following the fracture, >1 year following the fracture, or never and new osteoporotic fractures within 2 years after a pelvic fracture. Results From 2008 to 2014, 947 patients presented with pelvic fractures. Of these patients, 27.1% (257 patients) were taking anti-osteoporosis medications before the fracture. Four percent of treatment-naive patients began anti-osteoporosis therapy within 1 year of fracture, with 1.2% (11 patients) starting after 1 year. Of the treatment-naive patients, 92.3% (637 patients) were never prescribed anti-osteoporosis therapy. Treatment rates were consistent over time. Within 2 years, 41.0% (388 patients) developed fragility fractures at secondary sites: 12.0% (114 patients) experienced a hip fracture, and 16.4% (155 patients) experienced a vertebral fracture. Conclusions Osteoporosis screening and initiation of secondary fracture prevention after a pelvic fracture were inadequate in the study population. Of the patients in this study, 909 (96.0%) never underwent a dual x-ray absorptiometry (DXA) scan during the study period. Of the 690 treatment-naive patients, 637 (92.3%) were never administered anti-osteoporosis medications. Within 2 years, 41.0% of all patients developed additional osteoporotic fractures. This study demonstrates an opportunity to improve bone health by screening for and treating osteoporosis in patients with a pelvic fragility fracture. Level of evidence Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a median survival of just over one year. The failure of available treatments to achieve remission in patients with GBM has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence; in fact, the property of “stemness” itself may be responsible for treatment resistance. In this study, we identify a novel lncRNA, Cancer stem cell associated distal enhancer of SOX2 (CASCADES) that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in IDH-wild type GBM and significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs and represent a novel epigenetic and therapeutic target for disrupting the cancer stem cell compartment in GBM.

Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumour in children. To date, there are no effective chemotherapeutics despite a myriad of clinical trials. The intact blood-brain barrier (BBB) is likely responsible for the limited clinical response to chemotherapy. MRI-guided focused ultrasound (MRgFUS) is a promising non-invasive method for treating CNS tumours. Moreover, MRgFUS allows for the temporary and repeated disruption of the BBB. Our group previously reported the feasibility of temporary BBB opening within the normal murine brainstem using MRgFUS following intravenous (IV) administration of microbubbles. In the current study, we set out to test the effectiveness of targeted chemotherapy when paired with MRgFUS in murine models of DIPG. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics tested on patient-derived cell lines. We studied the RCAS/Tv-a model where RCAS-Cre, RCAS-PDGFB, and RCAS-H3.3K27M were used to drive tumourigenesis upon injection in the pons. We also used orthotopically injected SU-DIPG-6 and SU-DIPG-17 xenografts which demonstrated a diffusely infiltrative tumour growth pattern similar to human DIPG. In our study, SU-DIPG-17 xenografts were more representative of human DIPG with an intact BBB. Following IV administration of doxorubicin, MRgFUS-treated animals exhibited a 4-fold higher concentration of drug within the SU-DIPG-17 brainstem tumours compared to controls. Moreover, the volumetric tumour growth rate was significantly suppressed in MRgFUS-treated animals whose tumours also exhibited decreased Ki-67 expression. Herein, we provide evidence for the ability of MRgFUS to enhance drug delivery in a mouse model of DIPG. These data provide critical support for clinical trials investigating MRgFUS-mediated BBB opening, which may ameliorate DIPG chemotherapeutic approaches in children.