tbuckley/cabot-search huggingface dataset:
IMMU-64. A DECADE OF RESEARCH TARGETING IMMUNOSUPPRESSIVE IDO1 IN GLIOBLASTOMA: NEARING THE FINISH LINE OR JUST BEGINNING THE MARATHON?
Authors: Derek Wainwright
Journal: Neuro-Oncology (2018)

The Phase III ECHO-301/KEYNOTE-252 trial results showing that, the combination of PD-1 inhibitor (Keytruda), combined with the IDO1 enzyme inhibitor (epacadostat), fails to improve PFS, as compared to single-agent treatment with PD-1 inhibitor, alone, has led to a cascade of IDO1-inclusive clinical trial discontinuations; and raised critical questions for whether IDO1 inhibition is important to patients with cancer. The first in vivo report demonstrating an ability for IDO1 to suppress the immune response, was shown in a syngeneic mouse mastocytoma model (Uyttenhove et al., 2003; Nature Med.). The group demonstrated that, tumor cell IDO1 expression led to the suppression of cancer immunity. High expression for IDO1 was also detected in ~90% of human patient-resected glioblastoma (GBM) specimens. In 2012, I led a report showing that, wild-type C57BL/6 mice intracranially-injected with syngeneic GL261, and knocked down for IDO1 expression (GL261-IDO1kd), led to the spontaneous rejection of brain tumors (Wainwright et al., 2012; CCR). Strikingly, the same GL261-IDO1kd tumor grew out normally in mice deficient for CD4+ and/or CD8+ T cells, collectively confirming the immunosuppressive role of glioma cell IDO1. In 2017, my group demonstrated a number of novel observations that began questioning whether IDO1 enzyme activity suppresses the immune response, or rather, whether enzyme activity serves a proxy for an alternative, uncharacterized immunosuppressive mechanism (Zhai et al., 2017a; CCR, Zhai et al., 2017b; BBI). In 2018, we unexpectedly discovered that, IDO1 becomes targetable in non-tumor cells after treatment with ionizing radiation and PD-1 mAb. Strikingly, immunosuppression mediated by tumor cell IDO1, was unaffected by a pharmacologic IDO1 enzyme inhibitor. These cumulative data have prompted us to create novel transgenic models that will allow us to further understand how to effectively target IDO1 in glioblastoma, and potentially, to serve as valuable tools for the validation of second generation IDO1 inhibitors.
Abstract 18138: Endothelial PHD2 Loss Causes Pulmonary Arterial Hypertension via HIF-2 <i>(Best of Basic Science Abstract)</i>
Authors: Volker H Haase, James West, Pinelopi P Kapitsinou
Journal: Circulation (2015)

Background: Key mediators of cellular adaption to hypoxia are hypoxia-inducible factor (HIF)-1 and -2, which are regulated by the prolyl hydroxylases (PHDs). Although the HIF pathway has been shown to be involved in the pathogenesis of pulmonary arterial hypertension (PAH), little is known about the cell type-specific functions of the PHD/HIF axis in this context. Here, we used a genetic approach to specifically dissect the contribution of the endothelial PHD/HIF axis in PAH. Methods: Endothelial cell specific HIF activation was achieved by crossing Vecadherin (Cdh5)-Cre transgenics to Phd2 floxed mice (ePHD2), while the contribution of each HIF isoform was assessed by generating double mutants lacking PHD2 and HIF-2 (ePHD2HIF2) or PHD2 and HIF-1 (PHD2HIF1). Right ventricular systolic pressure (RVSP) was directly measured via insertion of a 1.4F Mikro-tip catheter transducer into a surgically exposed right internal jugular vein. Results: Mice deficient for endothelial PHD2 showed significant activation of HIF-signaling as shown by immunoblot analysis of lung tissue for HIF-1 and HIF-2. These mice developed spontaneous PAH (ePHD2: 54.3±6.9 vs Cre-: 24.8±2.2 mmHg, n=5-6, P=0.005) which was associated with right ventricular hypertrophy (RVH) (Fulton Index: 0.52 in ePHD2 vs 0.28 in Cre-, P=0.0004) and increased mortality. The PAH phenotype was maintained in ePHD2HIF1 mutants but was reversed in ePHD2HIF2 mutants. To assess the contribution of endothelial HIF-2 in hypoxia induced PAH, endothelial HIF-2 single mutants or Cre- littermates were exposed to normobaric hypoxia (10% O2) for 4 weeks. In contrast to controls, eHIF2 mutants were completely protected from development of PAH and RVH. Bone marrow transplantation studies showed no contribution from hematopoietic HIF-2 in hypoxia induced PAH. Conclusions: Our data establish that endothelial PHD2 loss results in PAH through a HIF-2 dependent mechanism. Our findings identify the PHD2/HIF2 axis as a potential target for PAH therapies.
PDTM-09. DIFFUSE INTRINSIC PONTINE GLIOMA AND PEDIATRIC GLIOBLASTOMA DERIVED-EXOSOMES HAVE SPECIFIC ONCOGENIC SIGNATURES
Authors: Giulia Pericoli, Angela Galardi, Lucia Lisa Petrilli, Marta Colletti, Roberta Ferretti, Alessandro Paolini, Andrea Masotti, Stefano Levi Mortera, Stefania Petrini, Emmanuel de Billy, Luisa Pascucci, Will Court, Antonella Cacchione, Andrea Carai, Francesca Diomedi Camassei, Andrew Moore, Angel Montero Carcaboso, Chris Jones, Angela Mastronuzzi, Franco Locatelli, Angela Di Giannatale, Maria Vinci
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) and pediatric glioblastoma (pGBM) are heterogeneous brain tumors characterized by different anatomical and molecular subgroups and the presence of genetically and phenotypically distinct subclonal cell populations. It is recognized that exosomes mediate cross-talk among tumor cells. We hypothesize that there are different exosome-mediated paracrine signaling promoting tumour progression in DIPG and pGBM. Our aim was to determine the specific DIPG and pGBM-derived exosome oncogenic signatures. We used a panel of fifteen patient primary-derived cell lines, which included nine DIPG (seven H3.3 K27M, one H3.3 K27M/ACVR1 and one H3.1 K27M/ACVR1), one diffuse midline glioma H3.3 K27M and three GBM (one H3.3 G34R and two histone WT). Conditioned medium was collected from cells maintained under stem-cell culture condition, adherent on laminin and/or as neurospheres (NS), and exosomes harvested through serial centrifugations. Electron microscopy demonstrated that the isolated microvescicles are exosomes sized between 50–80 nm. DIPG derived-exosomes appeared to have a variable cargo of total protein (µg)/106 cells, which was higher than for pGBM-exosomes. Proteomic analysis revealed that proteins associated with vesicle docking, exocytosis and synaptic transmission were exclusively enriched in pontine-derived exosomes, while cell-cell and cell-matrix interaction proteinswere exclusive tohemispheric ones. Proteins in common to the two locations were involved in metabolism and energy pathways. Interestingly, principle component analysis on the different molecular subgroups suggests that ACVR1 may be not implicated in the exosomal proteomic signature. Exosomal miRNA profile appeared to be driven by the two main histone mutated subgroups H3.3 K27M and H3.1 K27M with the latter overexpressing hypoxia and angiogenic-associated miRNAs, leading to distinct oncogenic programs with different specific potential therapeutic targets. This study aimed to development new diagnostic/prognostic tools for DIPG and pGBM patients. Further investigations are aimed to identify new therapeutic strategies to inhibit the cross-talk among glioma subpopulations.
Resurgence of Diabetes-Related Nontraumatic Lower-Extremity Amputation in the Young and Middle-Aged Adult U.S. Population
Authors: Linda S. Geiss, Yanfeng Li, Israel Hora, Ann Albright, Deborah Rolka, Edward W. Gregg
Journal: Diabetes Care (2018)

To determine whether declining trends in lower-extremity amputations have continued into the current decade.We calculated hospitalization rates for nontraumatic lower-extremity amputation (NLEA) for the years 2000-2015 using nationally representative, serial cross-sectional data from the Nationwide Inpatient Sample on NLEA procedures and from the National Health Interview Survey for estimates of the populations with and without diabetes.Age-adjusted NLEA rates per 1,000 adults with diabetes decreased 43% between 2000 (5.38 [95% CI 4.93-5.84]) and 2009 (3.07 [95% CI 2.79-3.34]) (P < 0.001) and then rebounded by 50% between 2009 and 2015 (4.62 [95% CI 4.25-5.00]) (P < 0.001). In contrast, age-adjusted NLEA rates per 1,000 adults without diabetes decreased 22%, from 0.23 per 1,000 (95% CI 0.22-0.25) in 2000 to 0.18 per 1,000 (95% CI 0.17-0.18) in 2015 (P < 0.001). The increase in diabetes-related NLEA rates between 2009 and 2015 was driven by a 62% increase in the rate of minor amputations (from 2.03 [95% CI 1.83-2.22] to 3.29 [95% CI 3.01-3.57], P < 0.001) and a smaller, but also statistically significant, 29% increase in major NLEAs (from 1.04 [95% CI 0.94-1.13] to 1.34 [95% CI 1.22-1.45]). The increases in rates of total, major, and minor amputations were most pronounced in young (age 18-44 years) and middle-aged (age 45-64 years) adults and more pronounced in men than women.After a two-decade decline in lower-extremity amputations, the U.S. may now be experiencing a reversal in the progress, particularly in young and middle-aged adults.
PATH-11. TRANSLATING GENOMIC DATA OF GLIOBLASTOMA INTO CLINICAL PRACTICE: A CASE STUDY
Authors: Toni Rose Jue, Julia Yin, Anna Siddell, Victor Lu, Robert Rapkins, Sylvia Chung, Shane Whittaker, Elizabeth Hovey, Jacob Fairhall, Kerrie McDonald
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), a malignant brain tumour that occur in adults and children, represents a major challenge for treatment. Tumor heterogeneity has been shown to contribute to this problem. The aim of this study was to overcome this issue by exploring an individualized treatment approach by selecting treatment options using whole genome sequencing, drug-screening panel and a network analysis. We present a case of a 51-year old female long-term GBM survivor with an unmethylated MGMT promoter gene who survived more than three years. Whole genome sequencing (WGS) revealed an ultra-mutated genotype in both primary and recurrent tumour samples with 421 substitutions per megabase. In depth analysis of the WGS revealed an average of 30 cancer driver genes were mutated with a 91% similarity in both primary and recurrent tumors. A drug screening panel and network analysis helped identify actionable targets. The drug screening panel included 165 compounds, of these we identified YM155, an experimental survivin inhibitor as a potential treatment. On the other hand, the network analysis revealed over 130 interconnected pathways affected by mutations in the driver genes. Pathways of interest were selected based on an FDR (false discovery rate) of 0.05 or less. These pathways included PTEN/PI3K/AKT pathway, DNA repair pathway, cell cycle pathway and various signaling pathways. EGFR was found to be predominant in 37% of the affected pathways. Hence, an EGFR inhibitor was recommended for treatment. Genome-guided treatment selection to individualize treatment for GBM patients was demonstrated to be possible in clinic. It remains a promising avenue for further translational research, with larger databases and integrated platforms to increase the efficiency of analyzing and interpreting the individual genomic data of GBM.
NIMG-73. RADIOMICS OF GLIOBLASTOMA FOR PREDICTING MGMT PROMOTOR METHYLATION STATUS AND PROGNOSIS
Authors: Takahiro Sasaki, Manabu Kinoshita, Koji Fujita, Hideyuki Arita, Takehiro Uda, Hisahiro Tsuyuguchi, Nobihude Hayashi, Junya Fukai, Yuji Uematsu, Kanji Mori, Yoshiko Okita, Masahiro Nonaka, Syusuke Moriuchi, Rintaro Hashizume, Naoyuki Nakao, Yonehiro Kanemura
Journal: Neuro-Oncology (2018)

O-6-methylguanine-DNA methyltransferase promotor methylation (pMGMT-met) is identified as a favorable prognostic factor for glioblastoma (GBM) and patients with GBM containing pMGMT-met benefit from temozolomide. On the other hand, radiomic analysis that rely on quantitative texture feature of radiological images has rapidly emerged in the field of neuro-oncology. In this study, the authors attempted to build a radiomic-based prediction model for pMGMT-met status of GB. Building a prognostic model was further attempted by radiomic analysis of conventional MRI. Preoperative MRI (non-enhanced and enhanced T1WI, T2WI, and FLAIR) from 207 newly diagnosed GBM (nGMB) patients were included in this study. Total of 489 texture features including first order feature (histogram of pixels), second order feature (Gray level co-occurrence matrix and Grey level run length matrix) from 166 date sets and location data from 187 data set were collected. Predictive modeling for pMGMT-met status was performed based on LASSO regression with 10-fold cross-validation which was repeated 5 times. Supervised component principal analysis was used for prognosis prediction. One hundred and four cases were pMGMT-met and 103 patients were MGMT promotor unmethylated (pMGMT-unmet). Predictive accuracy of pMGMT-met status was 68% modeled by 28 significant radiomic features. Furthermore, 20 radiomic features correlated with prognosis the analyzed cohort was categorized into high risk and low risk group by use of radiomic score (P value <0.0069). Radiomic score and pMGMT status were independent prognostic factors. Finally, significant survival difference was observed between radiomic high risk and pMGMT-unmet group, intermediated group (which group consists of radiomic low risk and pMGMT-unmet or radiomic high risk and pMGMT-met), and radiomic low risk and pMGMT-met group (P value <0.0001). In conclusion, the current study revealed that biological characteristics of GBM is embedded in radiomic features, recovery of which information could be beneficial for GBM patient care.
ANGI-04. TEAD1 REGULATES CELL MIGRATION IN HUMAN GLIOBLASTOMA IN PART THROUGH EMT-ASSOCIATED CADHERINS
Authors: Jessica Tome-Garcia, Parsa Erfani, German Nudelman, Rut Tejero, Roland Friedel, Elena Zaslavsky, Nadejda Tsankova
Journal: Neuro-Oncology (2018)

The epithelial to-mesenchymal transition (EMT) is a process by which epithelial cells gain migratory/invasive properties by upregulating pro-mesenchymal pathways, such as the expression of certain cadherin family proteins. Although a normal process during embryogenesis, EMT is often used by tumoral cells to increase their malignancy. In glioblastoma (GBM), a progressive glial tumor characterized by rapid growth and diffusely infiltrative spread, residing populations of glioma stem cells (GSCs) are thought to contribute to tumor invasiveness, EMT, and therapeutic resistance. To better understand GBM invasiveness in a developmental context, we used a recently described methodology to prospectively isolate human stem cell populations from GBM and germinal matrix tissues, and employed epigenetics to study their underlying transcriptional drivers. Analysis of RNA-seq in acutely-isolated GSC (vs. non-GSC) GBM populations revealed an upregulated EMT signature, with loss of “epithelial” markers, such as DSP and claudins (CLDN1, 7, 11, 12), and gain of mesenchymal markers, such as TNC and N-cadherin (CDH2). Chromatin accessibility mapping via ATAC-seq defined a tumor-specific signature related to migration, in which the TEAD1/4 transcription factor motif was the most highly and uniquely overrepresented in GSCs. Comparative analysis of ATAC-seq and RNA-seq data revealed several putative targets of TEAD1, and in vivo chromatin immunoprecipitation confirmed direct TEAD1 binding at the mesenchymal R-cadherin CDH4. Genetic ablation of TEAD1 in patient-derived GBM cells, using CRISPR-Cas9, reversed EMT transcriptome signature, diminished migratory properties in vitro, which were partially rescued after TEAD1 overexpression, and reduced profoundly infiltrative tumor burden in vivo after orthotopic xenotransplantation. CDH11 was one of the most downregulated mesenchymal cadherins after TEAD1 ablation, and its overexpression partially restored deficits in TEAD1-knockout cells related to cell migration, cell-cell adhesion, and substrate anchoring. Overall, our data validates a role for TEAD1 in GBM migration, mediated partially through the upregulation of EMT-associated cadherins.
MNGI-34. THE ROLE OF ALANINE AS A POTENTIAL METABOLIC MARKER IN DETECTING ATYPICAL MENINGIOMAS
Authors: Omkar Ijare, David Baskin, Kumar Pichumani
Journal: Neuro-Oncology (2018)

Meningiomas are tumors arising from meninges, the membranes surrounding the brain and the spinal cord. Majority of meningiomas (especially the grade-1) are benign and grow slowly. However, atypical meningiomas (grade-2) exhibit increased cellular proliferation, and grow at much faster rate than benign meningiomas. Moreover, atypical meningiomas have higher probability to recur compared to benign meningiomas. The goal of this study is to identify potential metabolic markers that can be used to distinguish meningioma tumors of grade-1 and atypical grade-2. We have collected tumor tissues from fifteen meningioma patients (grade-1 = 10 and grade-2 = 5) during surgical removal of the tumor mass at the Houston Methodist Hospital. We have employed ex vivo 1H magnetic resonance spectroscopy of tumor tissue extracts to determine whether there are any metabolic differences between grade-1 and grade-2 meningiomas. We have detected the following aqueous metabolites in the tumors that we have studied: leucine, isoleucine, valine, lactate, alanine, acetate, glutamate, succinate, glutamine, aspartate, creatine. phosphocreatine, phosphocholine/glycerophosphocholine, glycine, phosphoethanolamine, myoinositol, and glucose. Quantitative analysis of these metabolites revealed for the first time that alanine and glutamine were highly elevated in grade-2 meningiomas compared to grade-1 tumors. The levels of alanine and glutamine in grade-1 are 2.93 ± 1.20 and 4.81 ± 2.37 µmol/g, while in grade-2 tumors, the levels are 4.95 ± 2.47 and 7.13 ± 4.23 µmol/g respectively. Elevated levels of alanine has been detected previously in grade -1 meningioma patients. However, there has been no study to date that compares various metabolite levels between grade-1 and grade-2 (atypical) meningiomas. Glutamine-derived glutamate is known as the key precursor in alanine biosynthesis. We examine using a larger patient cohort whether there is any correlation between the levels of alanine and glutamine in meningiomas of these two grades.
ACTR-42. THE USE OF ADVANCED DIFFUSION MRI PARAMETERS IN THE ASSESSMENT OF TREATMENT RESPONSE IN GLIOBLASTOMA USING MULTI-B VALUE ACQUISITION AND A HISTOGRAM-BASED APPROACH
Authors: Shah Islam, Melanie Morrison, Matthew Grech-Sollars, Matthew Orton, Adam Waldman
Journal: Neuro-Oncology (2018)

PURPOSE: Imaging biomarkers to assess early treatment response in gliomas are important for guiding optimal clinical decision-making for individual patients, and as platforms for multi-institutional clinical trials of novel therapies. Current Response Assessment in Neuro-Oncology (RANO) criteria, rely on subjective, semi quantitative measurements with limited sensitivity and specificity in the early treatment phase. Previous diffusion imaging studies have indicated early sensitivity to treatment response, however optimum acquisition and analysis approaches have yet to be established. The purpose of this study is to assess the utility of advanced quantitative diffusion MRI derived from multi B-value acquisitions in the assessment of treatment response, using a spatially independent approach. We used least-square fitting to model six diffusion parameters from mono-, bi-, and stretch-exponential models, and performed a histogram analysis of voxels located within ROIs defined by enhancing tumour and increased signal on FLAIR sequences. Histograms were generated for 10 patients with GBM at 3 time-points before, at 6 weeks, and 3 months treatment with standard-of-care regimen (RT with concomitant and adjuvant temozolomide). Changes in the histograms percentile profiles were evaluated across the various time-points, back-projected onto MRI images for spatial correspondence, and compared with RANO assessment from structural MRI at the latest timepoint. RESULTS, DISCUSSION & CONCLUSION: Percentile profiles changed over the course of therapy, reflecting known biological changes in the tumour microenvironment in response to radiotherapy and chemotherapy; these preliminary data suggest differential changes in diffusion parameters early in treatment. Spatially-independent diffusion parameter comparisons abrogate the confound of voxel misregistration due to tumour growth/shrinkage. Further assessment of this dataset, augmented by on-going patient recruitment across multiple centres, will provide insight to the prognostic value of advanced diffusion MRI as a standardized method for treatment response assessment.
Effect of ten-valent pneumococcal conjugate vaccine introduction on pneumococcal carriage in Fiji: results from four annual cross-sectional carriage surveys
Authors: Eileen M Dunne, Catherine Satzke, Felisita T Ratu, Eleanor F G Neal, Laura K Boelsen, Silivia Matanitobua, Casey L Pell, Monica L Nation, Belinda D Ortika, Rita Reyburn, Kylie Jenkins, Cattram Nguyen, Katherine Gould, Jason Hinds, Lisi Tikoduadua, Joseph Kado, Eric Rafai, Mike Kama, E Kim Mulholland, Fiona M Russell
Journal: The Lancet Global Health (2018)

BackgroundThe indirect effects of pneumococcal conjugate vaccines (PCVs) are mediated through reductions in carriage of vaccine serotypes. Data on PCVs in Asia and the Pacific are scarce. Fiji introduced the ten-valent PCV (PCV10) in 2012, with a schedule consisting of three priming doses at 6, 10, and 14 weeks of age and no booster dose (3 + 0 schedule) without catch-up. We investigated the effects of PCV10 introduction using cross-sectional nasopharyngeal carriage surveys.MethodsWe did four annual carriage surveys (one pre-PCV10 and three post-PCV10) in the greater Suva area in Fiji, during 2012–15, of 5–8-week-old infants, 12–23-month-old children, 2–6-year-old children, and their caregivers (total of 8109 participants). Eligible participants were of appropriate age, had axillary temperature lower than 37°C, and had lived in the community for at least 3 consecutive months. We used purposive quota sampling to ensure a proper representation of the Fiji population. Pneumococci were detected by real-time quantitative PCR, and molecular serotyping was done with microarray.Findings3 years after PCV10 introduction, vaccine-serotype carriage prevalence declined, with adjusted prevalences (2015 vs 2012) of 0·56 (95% CI 0·34–0·93) in 5–8-week-old infants, 0·34 (0·23–0·49) in 12–23-month-olds, 0·47 (0·34–0·66) in 2–6-year-olds, and 0·43 (0·13–1·42) in caregivers. Reductions in PCV10 serotype carriage were evident in both main ethnic groups in Fiji; however, carriage of non-PCV10 serotypes increased in Indigenous Fijian infants and children. Density of PCV10 serotypes and non-PCV10 serotypes was lower in PCV10-vaccinated children aged 12–23 months than in PCV10-unvaccinated children of the same age group (PCV10 serotypes −0·56 [95% CI −0·98 to −0·15], p=0·0077; non-PCV10 serotypes −0·29 [–0·57 to −0·02], p=0·0334).InterpretationDirect and indirect effects on pneumococcal carriage post-PCV10 are likely to result in reductions in pneumococcal disease, including in infants too young to be vaccinated. Serotype replacement in carriage in Fijian children, particularly Indigenous children, warrants further monitoring. Observed changes in pneumococcal density might be temporal rather than vaccine related.FundingDepartment of Foreign Affairs and Trade of the Australian Government through the Fiji Health Sector Support Program; Victorian Government's Operational Infrastructure Support Program; Bill & Melinda Gates Foundation.