tbuckley/cabot-search huggingface dataset:
TAMI-34. SEX-SPECIFIC METABOLIC ADAPTATIONS TO THE KETOGENIC DIET IN A MOUSE MODEL OF GLIOBLASTOMA
Authors: Shanshan Zhang, Jasmin Sponagel, Joshua Rubin, Joseph Ippolito
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is a lethal brain tumor that has a higher incidence and mortality in males compared to females. GBM tumors consume glucose and glutamine as the major fuels for growth and strategies have been developed that disrupt these nutrient utilization pathways. Both pre-clinical and clinical reports have identified the ketogenic diet (KD) as an approach which consists of high fat and low carbohydrates. It reduces circulating glucose and increases ketones resulting in restricted tumor growth. Because of published studies showing that carbohydrate utilization is higher in healthy males, we hypothesized that the KD would have greater inhibition of male GBM growth. We compared sex differences in response to the KD using an established GBM mouse model (Nf1-/-DNp53), which has previously yielded important insights into sex differences in GBM. Flank tumors were implanted and tumor size measurements were performed. Unexpectedly, the KD had no effect on male GBM tumor growth, but female tumors grew significantly slower in mice that were on the KD compared to control diet. To understand how male GBM tumors adapt their metabolism to the KD, we measured serial blood glucose and ketone levels. We discovered expected physiologic responses to the KD with decreased serum glucose and increased serum ketones, suggesting that males adapt to the KD through changes in cell-intrinsic metabolism. Using FDG-PET imaging to investigate glucose utilization, we found that FDG uptake was increased in both tumor and normal brain of male but not female mice that were on the KD compared to control diet. Taken together, our results show that the KD has a greater impact on female GBM tumor growth and that sex differences in metabolic adaptations such as increased glucose transport may underlie the male-specific resistance to the KD. This study has the potential to develop sex-specific metabolic treatment approaches for GBM.
Changes in Drug List Prices and Amounts Paid by Patients and Insurers
Authors: Eric J. Yang, Emilio Galan, Robert Thombley, Andrew Lin, Jaeyun Seo, Chien-Wen Tseng, Jack S. Resneck, Peter B. Bach, R. Adams Dudley
Journal: JAMA Network Open (2020)

<h3>Importance</h3> High out-of-pocket drug costs can cause patients to skip treatment and worsen outcomes, and high insurer drug payments could increase premiums. Drug wholesale list prices have doubled in recent years. However, because of manufacturer discounts and rebates, the extent to which increases in wholesale list prices are associated with amounts paid by patients and insurers is poorly characterized. <h3>Objective</h3> To determine whether increases in wholesale list prices are associated with increases in amounts paid by patients and insurers for branded medications. <h3>Design, Setting, and Participants</h3> Cross-sectional retrospective study analyzing pharmacy claims for patients younger than 65 years in the IBM MarketScan Commercial Database and pricing data from SSR Health, LLC, between January 1, 2010, and December 31, 2016. Pharmacy claims analyzed represent claims of employees and dependents participating in employer health benefit programs belonging to large employers. Rebate data were estimated from sales data from publicly traded companies. Analysis focused on the top 5 patent-protected specialty and 9 traditional brand-name medications with the highest total drug expenditures by commercial insurers nationwide in 2014. Data were analyzed from July 2017 to July 2020. <h3>Exposures</h3> Calendar year. <h3>Main Outcomes and Measures</h3> Changes in inflation-adjusted amounts paid by patients and insurers for branded medications. <h3>Results</h3> In this analysis of 14.4 million pharmacy claims made by 1.8 million patients from 2010-2016, median drug wholesale list price increased by 129% (interquartile range [IQR], 78%-133%), while median insurance payments increased by 64% (IQR, 28%-120%) and out-of-pocket costs increased by 53% (IQR, 42%-82%). The mean percentage of wholesale list price accounted for by discounts increased from 17% in 2010 to 21% in 2016, and the mean percentage of wholesale list price accounted for by rebates increased from 22% in 2010 to 24% in 2016. For specialty medications, median patient out-of-pocket costs increased by 85% (IQR, 73%-88%) from 2010 to 2016 after adjustment for inflation and 42% (IQR, 25%-53%) for nonspecialty medications. During that same period, insurer payments increased by 116% for specialty medications (IQR, 100%-127%) and 28% for nonspecialty medications (IQR, 5%-34%). <h3>Conclusions and Relevance</h3> This study's findings suggest that drug list prices more than doubled over a 7-year study period. Despite rising manufacturer discounts and rebates, these price increases were associated with large increases in patient out-of-pocket costs and insurer payments.
The shared risk of diabetes between dog and cat owners and their pets: register based cohort study
Authors: Rachel Ann Delicano, Ulf Hammar, Agneta Egenvall, Carri Westgarth, Mwenya Mubanga, Liisa Byberg, Tove Fall, Beatrice Kennedy
Journal: BMJ (2020)

Abstract Objective To investigate whether dog and cat owners and their pets share a risk of developing diabetes. Design Cohort study. Setting Register based longitudinal study, Sweden. Participants 208 980 owner-dog pairs and 123 566 owner-cat pairs identified during a baseline assessment period (1 January 2004 to 31 December 2006). Main outcome measures Type 2 diabetes events in dog and cat owners and diabetes events in their pets, including date of diagnosis during the follow-up period (1 January 2007 to 31 December 2012). Owners with type 2 diabetes were identified by combining information from the National Patient Register, the Cause of Death Register, and the Swedish Prescribed Drug Register. Information on diabetes in the pets was extracted from veterinary care insurance data. Multi-state models were used to assess the hazard ratios with 95% confidence intervals and to adjust for possible shared risk factors, including personal and socioeconomic circumstances. Results The incidence of type 2 diabetes during follow-up was 7.7 cases per 1000 person years at risk in dog owners and 7.9 cases per 1000 person years at risk in cat owners. The incidence of diabetes in the pets was 1.3 cases per 1000 dog years at risk and 2.2 cases per 1000 cat years at risk. The crude hazard ratio for type 2 diabetes in owners of a dog with diabetes compared with owners of a dog without diabetes was 1.38 (95% confidence interval 1.10 to 1.74), with a multivariable adjusted hazard ratio of 1.32 (1.04 to 1.68). Having an owner with type 2 diabetes was associated with an increased hazard of diabetes in the dog (crude hazard ratio 1.28, 1.01 to 1.63), which was attenuated after adjusting for owner’s age, with the confidence interval crossing the null (1.11, 0.87 to 1.42). No association was found between type 2 diabetes in cat owners and diabetes in their cats (crude hazard ratio 0.99, 0.74 to 1.34, and 1.00, 0.78 to 1.28, respectively). Conclusions Data indicated that owners of a dog with diabetes were more likely to develop type 2 diabetes during follow-up than owners of a dog without diabetes. It is possible that dogs with diabetes could serve as a sentinel for shared diabetogenic health behaviours and environmental exposures.
TBIO-06. BDNF-TRKB SIGNALING REGULATES NEURON-GLIOMA SYNAPTOGENESIS AND PROMOTES TUMOR PROGRESSION
Authors: Kathryn Taylor, Helena Zhang, Alexa Hui, Shawn Gillespie, Michelle Monje
Journal: Neuro-Oncology (2020)

Abstract Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs hijack mechanisms of brain development and plasticity to their advantage. Here, we investigated the role of microenvironmental BDNF on pediatric gliomas, independent of the NTRK fusion events commonly identified in infant HGG. Genetic deletion or pharmacological blockade of NTRK2 (TrkB), in patient-derived pediatric glioma increases survival in multiple DIPG and pGBM patient-derived orthotopic xenograft models. Unlike the paracrine BDNF-TrkB signaling observed between subpopulations of adult HGG malignant cells, pediatric glioma express TrkB, but not BDNF ligand. BDNF is secreted by normal brain cells in response to neuronal activity and conditioned medium experiments from cortical slices of mice indicates the brain microenvironment as the chief source of BDNF ligand. Addition of recombinant BDNF protein increases pediatric glioma cell proliferation and activates the canonical downstream MAPK signaling pathway, an effect that is blocked by genetic or pharmacological TrkB inhibition in pHGG. However, the glioma growth-promoting effects of BDNF in vivo cannot be explained by stimulation of MAPK signaling alone. We therefore examined the effects of BDNF signaling on neuron-to-glioma synapse formation, a newly recognized microenvironmental interaction important for pediatric glioma progression. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis in neuron-glioma co-culture. We are presently exploring the role for BDNF-TrkB signaling in glioma synaptic plasticity and function. Funding: Abbie’s Army Foundation
Recent Trends, Construction, and Applications of Smart Textiles and Clothing for Monitoring of Health Activity: A Comprehensive Multidisciplinary Review
Authors: Jan Kubicek, Klara Fiedorova, Dominik Vilimek, Martin Cerny, Marek Penhaker, Miroslav Janura, Jiri Rosicky
Journal: IEEE Reviews in Biomedical Engineering (2020)

In the area of biomedical signal monitoring, wearable electronics represents a dynamically growing field with a significant impact on the market of commercial products of biomedical signal monitoring and acquisition, as well as consumer electronic for vital functions monitoring. Since the electrodes are perceived as one of the most important part of the biomedical signal monitoring, they have been one of the most frequent subjects in the research community. Electronic textile (e-textile), also called smart textile represents a modern trend in the wearable electronics, integrating of functional materials with common clothing with the goal to realize the devices, which include sensors, antennas, energy harvesters and advanced textiles for self-cooling and heating. The area of textile electrodes and e-textile is perceived as a multidisciplinary field, integrating material engineering, chemistry, and biomedical engineering. In this review, we provide a comprehensive view on this area. This multidisciplinary review integrates the e-textile characteristics, materials and manufacturing of the textile electrodes, noise influence on the e-textiles performance, and mainly applications of the textile electrodes for biomedical signal monitoring and acquisition, including pressure sensors, electrocardiography, electromyography, electroencephalography and electrooculography monitoring.
DIPG-31. MOLECULAR MECHANISMS AND FUNCTIONAL IMPACT OF ABERRANT SPLICING IN DIFFUSE MIDLINE GLIOMAS
Authors: Ammar Naqvi, Krutika Gaonkar, Yuankun Zhu, Miguel Brown, Bo Zhang, Brian Ennis, Phillip Storm, Adam Resnick, Jo Lynne Rokita
Journal: Neuro-Oncology (2020)

Abstract Fewer than 1% of children diagnosed with diffuse-midline glioma (DMG) survive for more than 5 years, because no effective therapies exist for these patients. Here, we sought to identify and characterize mechanisms of aberrant splicing (AS) in primary DMG tumors. We observed transcriptome-wide AS (9,805 differential splicing variations in 4,734 genes), and identified a DMG-specific splicing signature, that included known cancer genes. We hypothesize that AS of cancer genes play a role in DMG tumor formation. Assessing whether splicing factor dysregulation impacted known cancer transcripts, we discovered several splicing factors, including SRRM4, SRRM3 and RBFOX3 to be down-regulated in DMG. Additionally, we found an enrichment of binding motifs for these proteins within flanking regions of these mis-spliced exons. We also observed recurrent significant exon inclusion in tumor suppressor SMARCA4, an integral member of the SWI/SNF family of proteins involved in chromatin remodeling. Further, we identified AS in 16 of the 27 members of the SWI/SNF complex, including increased skipping of exon 7 in DPF2, representing a complete mRNA transcript switch in DMG. Since SRRM4, SRRM3 and RBFOX3 are known regulators for neural-specific microexons, we focused on microexon splicing changes, hypothesizing that these regulators may be driving microexon mis-splicing in these tumors. We identified 245 known microexons lost or gained in DMG. Moreover, a quarter of which were observed in known cancer genes, with the most frequent splice event causing gain of a clathrin-binding site in the tumor suppressor BIN1 with a concurrent loss of an out-of-frame microexon in the oncogene BAK1, presumably activating it. Altogether, our results suggest that aberrant splicing may be an alternative mechanism driving DMG tumorigenesis and we are currently molecularly validating a subset of these events with the overall goal of identifying novel therapeutic targets for DMG tumors.
DIPG-41. DISSECTING THE MECHANISTIC BASIS FOR <i>ACVR1</i> AND <i>PIK3CA</i> MUTATION CO-OCCURRENCE IN DIFFUSE MIDLINE GLIOMAS USING GENETICALLY ENGINEERED MOUSE MODELS
Authors: Annette Wu, Tak Mak, Jerome Fortin
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with a dismal prognosis. Most of these tumors carry K27M mutations in histone H3-encoding genes, particularly H3F3A and HIST1H3B. In addition, activating mutations in ACVR1 and PIK3CA co-occur in a subset of DMGs. To understand how these lesions drive the development of DMGs, we generated genetically engineered mouse models in which Acvr1G328V, Hist1h3bK27M, and Pik3caH1047R are targeted to the OLIG2-expressing cell lineage. Animals carrying Acvr1G328V and Pik3caH1047R, with (“AHPO”) or without (“APO”) Hist1h3bK27M, developed high-grade diffuse gliomas involving midline and forebrain regions. Neither Acvr1G328V nor Pik3caH1047R drove tumorigenesis by themselves, but Acvr1G328V was sufficient to cause oligodendroglial differentiation arrest, pointing to a role in the earliest stages of gliomas formation. Transcriptomic analyses of AHPO and APO tumors indicated a predominantly proneural and oligodendrocyte precursor-like gene expression signature, consistent with the corresponding human pathology. Genes encoding transcription factors (TFs) with dual roles in controlling glial and neuronal differentiation were upregulated in tumors. Some of these genes were mildly induced by Acvr1G328V alone. Functional experiments using CRISPR/Cas9-mediated gene editing in patient-derived cell lines confirmed a role for some of these TFs in controlling DMG cell fitness. Overall, our results suggest that Pik3caH1047R consolidates Acvr1G328V-induced glial differentiation arrest to drive DMG development and progression.
INNV-26. SERVICE RECONFIGURATION INTO AN URGENT ELECTIVE PATHWAY FOR THE MANAGEMENT OF GLIOBLASTOMA PATIENTS IMPROVES OUTCOMES, COSTS AND PATIENT EXPERIENCE AND ADJUNCT USE: A SINGLE CENTRE SIX YEAR REVIEW
Authors: Rosa Sun, Shivam Sharma, Colin Watts, Victoria Wykes
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastomas (GB) are grade four gliomas, the most common form of neoplasms arising in the brain. GBs are known for their aggressiveness; despite widespread research, limited advances have been made to improve survival. Between 2014–2019, a service reconfiguration for suspected GB referrals within our centre has been achieved. We have gone from a predominantly emergency admission and surgery based service for GB, to an urgent elective admission pathway. This is backed by weekly MDTs, neuro-oncology specialist led clinics, with imaging and pre-assessment clinic as part of a one-stop-shop model. Improved planning through elective admissions has also helped us achieve increased use of intra-operative adjuncts, including neuro-monitoring and the use of 5-ALA. The aim of this study is to describe a single centre experience of improvements made across six years through a combination of service reconfiguration and an increase use of intra-operative adjuncts. METHODS Patients with histological confirmed, primarily diagnosed GBs between 01/01/2014 and 31/12/2019 were extracted from the pathology database. Information including survival, treatment (surgical, oncological) and use of adjunct, admission status, length of stay (LOS), extent of resection and surgical complications were extracted manually. Inpatient admission costs were estimated. RESULTS From 2014 to 2019, we achieved an increase in elective admissions (28.1% to 90.3%, p&amp;lt; 0.001), which has led to a greater proportion of patients undergoing resective surgery (68.4% to 81.9%, p= 0.041), reduction in median length of stay (9 to 3 days, p &amp;lt; 0.001) and deceased overall costs. An increased use of intra-operative adjuncts has improved the proportion of total and gross resections (p&amp;lt; 0.001). CONCLUSIONS A switch from emergency to a MDT-based, urgent pathway with increased use of intra-operative adjuncts has resulted in improved technical outcomes and cost savings for the trust. This change has high potential to improve survival in patients on further follow-up.
DDEL-01. ENHANCING DRUG DELIVERY WITH MRgFUS FOR DIFFUSE INTRINSIC PONTINE GLIOMA MODEL
Authors: Joji Ishida, Saira Alli, Andrew Bondoc, Brian Golbourn, Nesrin Sabha, Kristina Mikloska, Dilakshan Srikanthan, Amanda Luck, Christian Smith, Kullervo Hynynen, James Rutka
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumor in children. To date, there have been no effective chemotherapeutics despite a myriad of clinical trials. The intact blood-brain barrier (BBB) in part is responsible for the limited clinical response to chemotherapy. MRI guided focused ultrasound (MRgFUS) is a promising non-invasive tissue ablative method for CNS tumors. Moreover, MRgFUS allows for the temporary disruption of BBB. Our first objective was to determine the feasibility and safety of temporary BBB disruption within the brainstem using MRgFUS following intravenous (IV) administration of microbubbles in vivo. Our second objective was to select effective chemotherapeutics against DIPG cell lines, and to examine their therapeutic effects with MRgFUS in a mouse model of DIPG which exhibits an intact BBB. The non-invasive opening of the BBB was determined in the brainstem of normal rodents using physiological monitoring and histological analysis. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics using SU-DIPG4 and SU-DIPG17 cell lines. We established SU-DIPG17 xenografts which demonstrated diffusely infiltrative tumor growth similar to human DIPG. By LC-MS/MS analysis, MRgFUS led to a 4-fold increase in doxorubicin concentrations within the brainstem tumors following IV administration when compared to IV administration alone, We demonstrated feasibility and safety of MRgFUS in the rodent brainstem and have shown that MRgFUS increases doxorubicin uptake in the brainstem of a rodent model of DIPG. These preclinical data will be helpful in designing clinical trials of BBB disruption using MRgFUS for DIPG in children.
QOL-24. DIFFERENTIAL IMPACT OF TUMOR LOCATION, LOCAL AND CRANIOSPINAL IRRADIATION ON NEUROPSYCHOLOGICAL LONG-TERM OUTCOME IN CHILDREN WITH MEDULLOBLASTOMA, EPENDYMOMA AND SUPRATENTORIAL PNET: A LONGITUDINAL MULTICENTER OUTCOME ASSESSMENT OF CHILDREN FROM THE HIT-2000 AND HIT-REZ TRIALS
Authors: Holger Ottensmeier, Paul G Schlegel, Matthias Eyrich, Bernhard Zimolong, Martin Mynarek, Katja von Hoff, Stefanie Frahsek, Rene Schmidt, Andreas Faldum, Johannes Wolff, Gudrun Fleischhack, Monika Warmuth-Metz, Jürgen Krauss, Rolf-Dieter Kortmann, Niels Galley, Joachim Kühl, Stefan Rutkowski
Journal: Neuro-Oncology (2020)

Abstract Neurocognitive deficits are frequent in childhood brain tumor survivors and affect mental intelligence, psychomotor and executive abilities. The differential impact of factors such as disease (location, histology) or treatment (local (LI) vs. craniospinal irradiation (CSI)) on these parameters is not fully understood. Between 2007–2011 and 2013–2017 300 testings were performed on-site by one neuropsychologist. Of these, 274 tests from n=208 children with medulloblastoma (MB), ependymoma (EP) and supratentorial embryonal tumors (SET) &amp;lt;4 years at diagnosis are currently included into the analysis. Applied tests included the Bayley II, WUEP-KD, K-ABC, tapping speed (TS), CPT_Hits/CPT_DT, and, as a new score, CPT_Power which integrates the latter. Treatment consisted of surgery and chemotherapy ± LI/CSI. All children receiving CSI and MB children with LI showed substantial deficits in general intelligence scores. In contrast, children with MB or SET without CSI/LI and those with EP receiving LI performed surprisingly well after 2 and 5 years follow-up. Motor function (TS) was reduced in all children except those with SET without irradiation. Of note, mental processing speed (as measured in CPT_Power) was not essentially reduced in MB and EP patients, indicating that mental processing is less affected than motor speed (TS) in children with infratentorial tumors. In conclusion, our data show that besides the established detrimental effects of CSI on general intelligence, infratentorial tumor location is a main risk factor for motor dysfunction irrespective of irradiation. Appropriate sensitive testing tools are warranted to assess cognitive function without the interfering influence of motor dysfunction.
QOL-57. SOUTHERN CALIFORNIA KAISER PERMANENTE PEDIATRIC NEURO-ONCOLOGY PROGRAM DEVELOPMENT
Authors: Hung Tran
Journal: Neuro-Oncology (2020)

Abstract KEY MESSAGE Standardization of care for subspecialty patients require centralization and support across multi-disciplinary groups within the Kaiser Permanente medical group, which is a large health maintenance organization (HMO) in the United States. BACKGROUND Prior to the development of a Pediatric Neuro-Oncology program, Southern California Kaiser Permanente pediatric neuro-oncology patients were routinely referred to respective regional academic centers for consultation. The process was not standard across the region, resulting in additional costs and differences in treatment recommendations, potentially affecting outcomes. METHODS A Pediatric Neuro-Oncology program was established, July 2017, based at the Kaiser Permanente Los Angeles Medical Center (LAMC), consisting of pediatric neuro-oncology, pediatric neurosurgery, pediatric neuro-radiology, pediatric radiation oncology, and pediatric neuro-oncology case management. RESULTS A Pediatric Neuro-Oncology tumor board was established to meet on a bi-monthly basis. Pediatric neuro-oncology patients across the Southern California now have their magnetic resonance imaging (MRI) reviewed by the same pediatric neuro radiologists. Neuropathology is standardized and sent to Children’s Hospital Los Angeles and reviewed at the molecular neuropathology tumor board attended by the pediatric neuro-oncologist. Cases discussions regarding the patients include the regional pediatric neurosurgeons, the pediatric radiation oncologists, and the pediatric neuro-oncologist, and treatment plans are recommended and recorded by the case manager. CONCLUSIONS Centralization of care has allowed for more consistent and standard care across the Southern California Region, but requires support from multi-disciplinary groups.
Diabetes and Vascular 18F-Fluorodeoxyglucose Positron Emission Tomography Uptake: Another Step Toward Understanding Inflammation in Atherosclerosis⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: John O. Prior
Journal: Journal of the American College of Cardiology (2012)