tbuckley/cabot-search huggingface dataset:
STEM-25. SINGLE-CELL SIGNATURES UNCOVER GLIAL PROGENITOR HETEROGENEITY AND MOLECULAR DETERMINANTS FOR GLIOMA GROWTH
Authors: Richard Lu, Jincheng Wang, Jiajia Wang
Journal: Neuro-Oncology (2018)

The major glial subtypes in the brain, oligodendrocytes and astrocytes, are heterogeneous populations, however, their progenitor diversity and contribution to malignant transformation remain elusive. Despite recent progress in the evaluation of oligodendrocyte and astrocyte heterogeneity in adult brain regions, the diversity and molecular profiles of their progenitors remains incompletely understood. In addition, a comprehensive understanding of transcriptional dynamics of glial progenitors and their lineage determinants underlying normal development and malignant transformation is currently lacking. To address the heterogeneity of glial progenitors, we performed targeted high-throughput single-cell RNA sequencing of prospective astrocyte lineage cells and oligodendrocyte precursor populations isolated by fluorescence activated cell sorting from the neonatal cortices and mapped single-cell expression profiles and molecular features of glial subtype progenitors. We found that astrocyte lineage cells are much more dynamic than previously appreciated and exhibit distinct lineage developmental trajectories in the developing neonatal cortex. In contrast to the astrocyte lineage, the progenitors of oligodendrocytes (OPC) exhibited a cellular continuum, which included a previously unrecognized primitive OPC subpopulation prior to the committed OPCs. Application of scRNA-seq to a murine model of malignant glioma revealed cycling OPC serving as a specific cellular niche contribute to glioma formation. We also established a new algorithm to identify transcription-factor-driven networks and discovered a set of regulators critical for controlling glial lineage specification and glioma growth. Thus, our single-cell analyses reveal distinct dynamics and heterogeneity of glial progenitors during brain development. Moreover, we identify analogous glial progenitors as the important source for glioma growth, and further define a molecular link between gliogenesis and gliomagenesis, thereby pointing to potential cellular and molecular targets for glioma treatment.
Abstract P066: Tobacco Smoking After Diagnosis of Diabetes and the Risk of Diabetic Nephropathy
Authors: Hyungseon Yeom, Jung Hyun Lee, Hyeon Chang Kim, Il Suh
Journal: Circulation (2016)

Introduction: Smoking is known to be associated with the risk of nephropathy in patients with diabetes. However, the effect of smoking before or after the diagnosis of diabetes is not well known. Hypothesis: The effect of cigarette smoking before and after the diagnosis of diabetes on the presence of diabetic nephropathy would be different. Methods: We analyzed the 2011 - 2013 Korea National Health and Nutrition Examination Survey. Total 1,259 subjects diagnosed with diabetes were classified into 658 non-smokers, 247 smokers who did not smoked after the diagnosis of diabetes and 354 smokers who continued smoking after the diagnosis of diabetes. Diabetic nephropathy was defined as the presence of albuminuria (spot urine albumin/creatinine ratio ≥ 30 mg/g) or low estimated glomerular filtration rate (&lt; 60 mL/min/1.73 m 2 ). Multivariate logistic regression models were used to assess the independent association after adjusting for age, duration of diabetes, HbA1c, body mass index, blood pressure and dyslipidemia. Results: Compared to non-smokers, male patients who continued smoking after diagnosis of diabetes had a significantly higher odds ratio (2.17, 95% CI 1.23 to 3.83) for the presence of diabetic nephropathy. The corresponding odds ratio for male patients who smoked before the diagnosis of diabetes but not after was 1.26 (95% CI, 0.70 to 2.29). However in female, we did not observed this association probably due to small number of smokers. Conclusions: Smoking, especially smoking after the diagnosis of diabetes, is associated with the presence of diabetic nephropathy. Our findings reaffirm that smoking cessation should be strongly recommended to patients with diabetes who smoke.
CBMT-20. A KETOGENIC PILL FOR GLIOBLASTOMA
Authors: Hassan Azari, Angela Poff, Dominic D’Agostino, Brent Reynolds
Journal: Neuro-Oncology (2018)

INTRODUCTION: While the KD holds promise as a therapeutic option for brain cancer patients, stringency of the diet impacts compliance. We have previously demonstrated that a high fat/low carbohydrate diet, similar to the Ketogenic Diet [KD], can reduce tumor progression and enhance survival in an orthotopic xenograft model. However, while this diet is less restrictive than the classic KD it still involves significant changes to a patient’s diet. Two of the primary physiological changes that occur when on the KD are a reduction in glucose and an increase in ketone bodies. These physiological changes are mimicked by providing ketone esters [KE] in the diet, and we [AMP, DPD], have recently shown that ketone esters can reduce glucose, elevate ketone bodies and enhance survival in a metastatic cancer model. HYPOTHESIS: We hypothesize that KE [1,3 butanediol acetoacetate diester] will reduce glucose, elevate ketones, reduce tumor progression and enhance survival in an orthotopic xenograft GBM model using a PDX model. APPROACH: NON/SCID animals implanted with patient-derived GBM cells were fed a standard diet [SD], or SD + KE [20%] till they reached endpoint. Body weight, plasma glucose, and ketones were measured weekly and overall survival assessed. While the KE is bitter and can have poor compliance, we found that supplementing with 1% Stevia increased palatability based on food consumption and body weight. Comparing to SD, KE supplemented diet reduced plasma glucose (145.5 ± 5.3 vs 121.7 ± 5.7), increased ketone bodies [ß-hydroxybutarate, 0.7 ± 0.15 vs.1.3 ± 0.1] and enhanced median survival [47 ± 6.2 vs 60.8 ± 1.9, days]. CONCLUSION: Ketone esters can be effectively delivered orally together with a standard diet, and produce similar physiological changes [reduction in glucose and elevation in ketones] and enhance survival as the more restrictive KD in NON/SCID animals.
Abstract 16323: Hyperhomocysteinemia Potentiates Type 2 Diabetes-induced Inflammatory Monocyte Differentiation and Vascular Dysfunction
Authors: Pu Fang, Meghana Pansuria, Xiaohua Jiang, Xiao-Feng Yang, Hong Wang
Journal: Circulation (2015)

Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. Soinio M et al. showed that coronary heart disease death was increased from 13.5% to 26.1% in type 2 diabetes mellitus (T2DM) subjects with HHcy. However, the role and underlying mechanism of HHcy in T2DM associated atherosclerosis remains unknown. To examine this, we established a mouse model with both HHcy and T2DM by feeding db/db mice (blood glucose level 493 mg/dL) a high fat+high methionine (HF+HM) diet (methionine is homocysteine (Hcy) precursor). The HF+HM diet induced severe HHcy in the control (CT) mice (129 μM) and T2DM mice (180 μM), which was lowered by vitamin supplement therapy via feeding the mice a HF+HM+high vitamin (HF+HM+HV) diet to 42 μM and 87 μM in CT and T2DM mice, respectively. We found HHcy and T2DM individually impaired endothelial-dependent vessel relaxation. HHcy worsened T2DM-impaired endothelial-dependent vessel relaxation in the aorta. More, HHcy and T2DM individually increased circulating mononuclear cell (MNC), CD11b + MNC (monocyte, MC), CD11b + Ly6C middle+high inflammatory MC, and M1 macrophage (MØ). HHcy potentiated T2DM-increased circulation MNC, MC, inflammatory MC, and M1 MØ. Similar cellular changes were observed in the bone marrow and spleen. It is evident that HHcy induced system inflammation as HHcy increased the levels of inflammatory cytokines in the CT and T2DM mice. Importantly, we found HHcy increased CD11b + Ly6C middle+high inflammatory MC infiltration in the aortas from mice with/out T2DM. Hcy-lowering therapy reversed HHcy-related MNC, MC, inflammatory MC and MØ induction in the system and reversed inflammatory MC infiltration in the vessel in mice with/out T2DM. In addition, peripheral and vessel wall inflammatory MC were positively correlated with plasma Hcy levels and negatively correlated with plasma s-adenosylmethionine/s-adenosylhomocysteine ratio, which is a methylation indicator. In conclusion, our study suggested that HHcy and T2DM induces systemic inflammation and promotes MC-derived vascular inflammation, which may contribute to vascular dysfunction. This HHcy-induced inflammatory MC differentiation, at least in part, via hypomethylation-related mechanisms.
PATH-40. TARGETED NEXT GENERATION SEQUENCING (NGS) OF YOUNG ADULTS WITH ISOCITRATE-DEHYDROGENASE WILD-TYPE GLIOBLASTOMA (IDH-WT GBM) REVEALS NEGATIVE PROGNOSTIC IMPACT OF EPIDERMAL GROWTH FACTOR RECEPTOR AMPLIFICATION (EGFRAMP)
Authors: Daniel Hoffman, Kalil Abdullah, Zev Binder, Donald O’Rourke, Arati Desai, Jennifer Morrissette, Steven Brem, Stephen Bagley
Journal: Neuro-Oncology (2018)

Young adults with IDH-WT GBM represent a rare, understudied population compared to pediatric, IDH-mutant, or typical (elderly) GBM. We aimed to explore clinically detected genomic alterations in this population and their prognostic impact. We identified patients ages 21 45 with newly diagnosed, previously untreated IDH-WT GBM whose tumors underwent NGS at our institution. Patients with hereditary cancer syndromes were excluded. The NGS panel detects pathogenic variants by targeted exome sequencing of 47 (2014–2016) or 153 (2016-present) genes. Clinical characteristics and overall survival (OS) were collected. These data were also collected from a contemporaneous cohort of older (>=65) patients with newly diagnosed, IDH-WT GBM. 28 young and 30 older patients were included. In young patients, 12 (43%) had an EGFR alteration [2 (7%) EGFR mutation, 7 (25%) EGFR amplification (EGFRamp), and 3 (13%) both EGFRamp and EGFRvIII]. Other mutations detected in 2 young patients were TP53 in 7 (25%), BRAF (V600E) in 3 (11%), RB1 in 3 (11%), PTEN in 2 (7%), SETD2 in 2 (7%), and DNMT3A in 2 (7%). Differences detected in older vs. younger patients were more frequent PTEN mutations (27% vs. 7%, p=0.049) and MGMT methylation (50% vs. 25%, p =0.06). In young patients, median OS was 19.5 months (95% CI 15.9–24.4), and EGFRamp was associated with inferior median OS (16.3 vs. 23.5 months, p=0.047). There was no difference in OS by EGFRamp in older patients. CONCLUSIONS: EGFRamp was associated with inferior OS in this contemporary cohort of young adults with IDH-WT GBM, whereas no association was detected in older patients. This suggests a potential role for targeting EGFR specifically in this population. In addition, consistent with prior studies, we found that MGMT methylation is less common in young patients with IDH-WT GBM, highlighting the need for alternatives to temozolomide.
DDIS-16. ONC201 IN COMBINATION WITH RADIATION EXHIBITS SYNERGISTIC EFFICACY IN HIGH GRADE GLIOMAS AND OTHER ADVANCED CANCERS
Authors: Rohinton Tarapore, Sachin Jhawar, Mark Stein, Bruce Haffty, Andrew Zloza, Sabine Mueller, Jie Zhang, Francesca Amoroso, Ian Mills, Wolfgang Oster, Joshua Allen
Journal: Neuro-Oncology (2018)

ONC201 is the first small molecule DRD2 antagonist for oncology that is being investigated as a single agent in advanced cancer clinical trials. Downstream of DRD2 antagonism, ONC201 activates the integrated stress response pathway and apoptosis. ONC201 has exhibited preclinical and clinical anti-tumor activity in high grade gliomas. Given that ONC201 exhibits broad synergy with anti-cancer drugs, excellent safety, and single agent activity in tumor types where radiation is used routinely, we evaluated the combination of ONC201 with radiation in solid tumors. Cell viability was evaluated in human and/or mouse breast, prostate and high-grade glioma cell lines in response to ONC201 (1 -10uM), radiation (2– 10Gy), or the combination. Incubation times ranged from 24 to 96 hours and the sequence of the two agents in combination was varied. Cell viability assays for ONC201 in combination with radiation in breast or prostate cancer cell lines revealed a cytotoxic response to the combination than was superior to either single agent. Western blot analysis of PC3 cells showed a synergistic induction of CHOP and ATF6 that are components of the integrated stress response. In MDA-MB-468 cells, Western blot analysis demonstrated a striking induction of PARP cleavage, a marker of caspase-mediated apoptosis, with 2 µM ONC201 in combination with 2 Gy radiation, whereas either single agent produced minimal PARP cleavage. In 4T1 murine triple-negative breast cancer subcutaneous tumors, the combination of oral ONC201 and radiation produced antitumor effects at subtherapeutic doses. In diffuse intrinsic pontine glioma cell lines, combination indices computed from cell viability experiments indicated modest synergy (~0.7 CI) for the combination ranging between 1–5 µM ONC201 and 2–10 Gy. ONC201 combines synergistically with radiation in high grade gliomas and other solid tumors.
Abstract 15481: LV Systolic Dysfunction is Improved by TAVR: Insights From the French-American Registry
Authors: Abdulla Damluji, Yahya E Alansari, Michael Dyal, Magdalena Murman, Mohamad Kabach, Italo Novoa, Shawn C Simek, Shawn C Simek, Rogerio Carrillo, Donald Williams, Eduardo J De Marchena, Claudia A Martinez, Carlos E Alfonso, Mauro Moscucci, Mauricio G Cohen, Lionel Leroux, Alan W Heldman
Journal: Circulation (2015)

Introduction: We sought to describe changes in left ventricular ejection fraction (LVEF) after TAVR procedures. Methods: This is an observational study from 04/2008 to 06/2015 of all consecutive adults who received TAVR for severe symptomatic AS with Edwards Sapien or Medtronic CoreValve at two tertiary academic centers in USA and France. Results: Of 765 patients who received TAVR, 716 (94%) had follow-up echocardiography. Of those, 513 (72%), 143 (20%), 60 (8%) had a baseline EF&gt;50%, EF 30-49%, and EF&lt;30, respectively. Patients with EF &lt; 30% were more likely to be Hispanic males. There were no differences in age, CVD risk factors, or history of multivessel coronary disease among groups. Patients with EF&lt;30% were more likely to have AICD implantation and paced rhythm. All groups had similar rates of IABP insertion for hemodynamic support (EF≥50%: 6%, EF&lt;30-49%: 9%, EF&lt;30: 5%, p=0.544), procedural success (EF≥50%: 94%, EF&lt;30-49%: 97%, EF&lt;30: 98%, p=0.180), in-hospital mortality, procedural complications, and complete heart block. However, one-year all-cause-mortality was higher if baseline LV systolic function was abnormal (EF≥50%: 6%, EF&lt;30-49%: 14%, EF&lt;30: 9%, p=0.036). On 30-day follow-up echocardiography, absolute improvement in LVEF was highest among patients with EF&lt;30% (Figure 1). If baseline LVEF was reduced, unchanged or improved mitral regurgitation were associated with improved LV function on follow-up (Figure 2). Conclusion: Transcatheter treatment of severe symptomatic AS is safe and feasible, even in patients with LVEF&lt;30%. Most patients with LVEF&lt;50% had increased EF after TAVR procedures.
NCMP-31. RISK OF INTRACRANIAL HEMORRHAGE (ICH) IN PATIENTS WITH HIGH-GRADE GLIOMA (HGG) ON THERAPEUTIC LOW MOLECULAR WEIGHT HEPARIN (LMWH)
Authors: Jasmin Jo, Joseph Donohue, Gina Petroni, David Schiff
Journal: Neuro-Oncology (2018)

Venous thromboembolism (VTE) occurs in 20–30% of HGG patients. The potential increased risk of ICH with therapeutic anticoagulation complicates VTE treatment. Recent retrospective study reported a 3-fold increased risk of ICH with therapeutic anticoagulation. Our study examines whether the administration of LMWH for VTE treatment is associated with increased risk of ICH in HGG patients. We performed a retrospective cohort study of HGG patients from 1/2005–8/2016. Patients in the LMWH group initiated treatment after VTE diagnosis. Blinded review of neuroimaging for ICH was performed. Patient characteristics were summarized using frequency for categorical variables and mean for continuous variables. For analysis of the primary end point, estimates of cumulative incidence (CI) of ICH were calculated using competing risk analysis with death as competing risk; significance testing was performed using the Gray’s test. A total of 174 patients (100 men) were included, 88 (51%) in the LMWH group and 86 (49%) in non-LMWH group. Within the non-LMWH group, 22 (26%) patients developed VTE but were not treated with anticoagulation, while 64 (74%) patients did not develop VTE. A total of 34 ICH were recorded: 19 (56%) in LMWH group, 3 (9%) in non-LMWH with VTE, and 12 (35%) in patients without VTE.No significant difference was observed in the 1-year CI of ICH in the LMWH cohort and non-LMWH with VTE group (17% versus 9%; Gray’s test, p=0.36). Among patients without VTE, the 1-year CI of ICH was 13%; direct comparison to LMWH group was not performed due to different starting time point of events. CONCLUSIONS: Contrary to recent studies, our data do not suggest that therapeutic LMWH is associated with significantly increased risk of ICH in HGG patients.
Abstract MP096: Patterns of Physical Activity Across Pregnancy and Their Association With Adverse Pregnancy Outcomes
Authors: Janet M Catov, Corette B Parker, Bethany B Gibbs, Carla Bann, Benjamin Carper, William A Grobman
Journal: Circulation (2017)

Background: Cardiovascular disease (CVD) is the leading cause of death among women, and pregnancy complications reveal risk decades before overt CVD. While physical activity is related to CVD, less is known about how the activity patterns during pregnancy may contribute to adverse pregnancy outcomes. Hypothesis: Increasing activity across pregnancy is related to reduced risk of adverse pregnancy outcomes. Methods: Nulliparous women were enrolled at 8 centers early in pregnancy (n=10,020). Frequency and duration of up to three leisure activities reported in the first, second and third trimester were analyzed as metabolic equivalents (METs). Growth mixture modeling was used to identify activity patterns in pregnancy. Adverse outcomes (preterm birth [PTB], hypertensive disease of pregnancy [HDP], and gestational diabetes [GDM]) were collected by chart abstraction. Results: Four patterns of activity across pregnancy were identified: sustained high (3%, n=297); increasing (12%, n=1231); sustained low (77%, n=7717); and decreasing (8%, n=775; Figure). Women with sustained low activity were younger and more likely to be black or Hispanic, obese, or to have smoked prior to pregnancy when compared to those with increasing activity. Women with sustained low vs. increasing activity had higher rates of PTB (9.2 vs. 6.2%), HDP (13.8 vs. 10.5%), and GDM (4.7 vs. 2.5%; all p &lt;0.01). After adjusting for maternal factors (age, race/ethnicity, BMI and smoking), the risk of GDM remained higher in women with sustained low activity compared with those having increasing activity patterns (adjusted OR 1.79 [1.21, 2.66]). Sustained low activity was also associated with higher risk of PTB (adjusted OR 1.36 [1.05, 1.76]). Conclusion: The majority of women have sustained low activity across pregnancy, and this is independently associated with higher risks of GDM and PTB. These associations raise the possibility that increased activity during pregnancy may improve pregnancy outcomes, and perhaps long-term maternal cardiovascular health.
PATH-07. PRONEURAL GLIOMAS ARE ASSOCIATED WITH POOR SURVIVAL AND MORE LIKELY LOCATED IN PROXIMITY TO THE SUB-VENTRICULAR ZONE
Authors: Rushikesh Joshi, Ali Alattar, Clark Chen
Journal: Neuro-Oncology (2018)

The Cancer Genome Atlas (TCGA) revealed five sub-classes of astrocytic gliomas; four sub-classes defined by RNA expression (proneural, neural, mesenchymal, and classical), and one by isocitrate dehydrogenase mutation (IDHm). These studies demonstrated prognostic differences only with IDH mutation. Using additional patient and clinical characteristics, we determine if there is a difference in survival between the non-IDH mutated molecular sybtypes of GBM, while accounting for patient age, KPS, or tumor grade. We identified 1,073 patients with astrocytomas of all grades from TCGA, excluding IDHm tumors to examine the potential association between RNA expression-based subtype classifications without IDHm as a confounder. We assessed survival using univariate and multivariate Cox proportional hazards analyses adjusted for age, KPS, and tumor grade. We also used The Cancer Imaging Archive (TCIA) to examine the relationship between molecular subtype and propensity for neuroanatomic location of glioblastomas (GBM). Univariate analyses indicated improved survival with increasing KPS (HR = 0.961, p< 0.001), and worse survival with increasing age (HR = 1.054, p< 0.001) and increasing grade (HR = 3.319, p = 0.004 for grade 3; HR = 11.432, p< 0.001 for GBM; relative to grade 2). While no survival association was observed with regards to the RNA-based subtype classification in univariate analysis, in a multivariate analysis that included age, KPS, tumor grade, and RNA-based subtype classification, proneural glioblastomas are associated with worse survival (HR = 1.524, p = 0.012) relative to the non-proneural glioblastomas. Additionally, analysis of TCIA demonstrated that proneural glioblastomas were more likely to be located near the sub-ventricular zone (SVZ, p< 0.05). Our findings suggest that RNA expression-based subtype classification has prognostic utility, and proneural subtype of astrocytoma is associated with worse survival. This subtype was more likely to be located near the SVZ, suggesting potential mechanistic insights for this survival association.
Abstract 18445: Autopsy-Defined Causes of Death by Sex and Race in the San Francisco POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) Study
Authors: Satvik Ramakrishna, Eric Vittinghoff, Annie Bedigian, Joanne Probert, Jeffrey E Olgin, Philip C Ursell, Ellen Moffatt, Zian H Tseng
Journal: Circulation (2017)

Introduction: Sudden cardiac death (SCD) incidence is higher in men and Blacks, with limited data for Asians and Hispanics, but prior studies have inferred causes of death (COD) from EMS records or...
A Prospective Analysis of Breakthrough Hemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria
Authors: Robert A. Brodsky, Regis Peffault De Latour, Scott T. Rottinghaus, Alexander Röth, Antonio M. Risitano, Ilene C. Weitz, Peter Hillmen, Jaroslaw P. Maciejewski, Jeffrey Szer, Jong-Wook Lee, Austin G. Kulasekararaj, Lori Volles, Andrew I. Damokosh, Stephan Ortiz, Lori Shafner, Anita Hill, Hubert Schrezenmeier
Journal: Blood (2018)