tbuckley/cabot-search huggingface dataset:
Abstract 19598: Estimation of Population Sodium Intake in Different Countries: Comparison of 24-h Dietary Recall With 24-h Urine Collection
Authors: Xiaoxiao Wen, Jeremiah Stamler, Linda Van Horn, Martha L Daviglus, Alan R Dyer, Paul Elliott, Queenie Chan, Hirotsugu Ueshima, Katsuyuki Miura, Nagako Okuda, Yangfeng Wu, Liancheng Zhao
Journal: Circulation (2015)

Introduction: Twenty-four-hour (24-h) urine excretion is the “gold standard” for estimation of sodium intake. Sodium intake assessed by 24-h dietary recall has been reported to correlate with urinary sodium excretion, and is considered reliable for assessing population sodium intake. However, the validity of 24-h dietary recall across countries has rarely been studied. The present study aims to compare the 24-h dietary recall with 24-h urine collection for the estimation of population sodium intake in different countries. Methods: Data from the International study of Macro- and Micro-nutrients and Blood Pressure (INTERMAP) were used in the analyses, including 4680 men and women ages 40-59 years from 17 population samples in China, Japan, UK and USA. Four 24-h dietary recalls and two timed 24-h urine samples were collected for each participant; the averages of the dietary and urinary sodium measurements were used. The correlation and difference between the two methods were then explored and compared across countries. Results: After adjustment for population sample and gender, a significant correlation was found in all four countries between dietary and urinary sodium measurements (r=0.33, 0.45, 0.36 and 0.46 for China, Japan, UK and USA respectively, P&lt;0.01 for all). The mean difference of sodium measurements between dietary recalls and urine collection was small for Japan (3.9 mmol), UK (2.9 mmol), and USA (-3.5 mmol), whereas it was large for China (-54.0 mmol). Further, population average sodium intake was over- or under-reported by about 2% for Japan, UK and USA participants with use of urinary sodium excretion as the reference, while the sodium intake was under-reported by 24% for Chinese. Conclusions: The correlation of sodium intake estimated by the two methods is similar (0.33-0.46) for the four countries, and the 24-h dietary recall data demonstrate great accuracy in assessing sodium intake at the population level for Japan, UK and USA. For Chinese populations, however, the 24-h urine collection is preferable to the 24-h dietary recall since dietary recalls yielded considerable underestimation of sodium intake.
GENE-13. GENOMIC FUNCTIONAL ENHANCERS DEFINE POTENTIAL TUMORIGENESIS OF G-CIMP-LOW (IDH-MUTANT ASTROCYTOMA) TUMORS INDEPENDENT OF PROMOTER METHYLATION
Authors: Thais Sabedot, Ana deCarvalho, Laila Poisson, James Snyder, Tobias Walbert, Ian Lee, Steven Kalkanis, Benjamin Berman, Houtan Noushmehr
Journal: Neuro-Oncology (2018)

Glioma CpG-island methylator phenotype (G-CIMP) is associated with IDH mutation and presents better clinical outcomes than for IDH wildtype gliomas. However, a recent stratification of G-CIMP tumors identified a subgroup of patients with distinct epigenetic changes in intergenic regions linked to poor prognosis (G-CIMP-low) compared to G-CIMP-high. Several regulatory elements, such as enhancers and silencers, are located outside gene promoters and DNA methylation changes in these elements could play an important role in regulating the expression of distant genes. In order to identify potential active enhancers by loss of DNA methylation in G-CIMP-low, we investigated 1 G-CIMP-low, 2 G-CIMP-high and 2 non-tumor brain samples profiled by whole-genome bisulfite sequencing (methylome) and RNA-sequencing (transcriptome). Using the GeneHancer database, which includes known enhancers and their potential gene targets assessed by functional studies, we identified 109 downregulated and 856 upregulated genes in G-CIMP-low in relation to G-CIMP-high. These had no DNA methylation differences at their promoters between G-CIMP-low, G-CIMP-high and non-tumor brain samples. However, the associated candidate enhancers for these genes had distinct hyper or hypo-methylation of CpG specific to G-CIMP-low, compared to both G-CIMP-high and non-tumor brain samples. Downregulated genes are associated with negative regulation of both protein phosphorylation and immune response, such as PRKAG2, an AMP-activated protein kinase. G-CIMP-low tumors have expression levels similar to IDH wildtype glioblastomas whereas G-CIMP-high tumors are comparable to non-tumor brain samples. Upregulated genes are enriched for cell cycle and metabolism of RNA, which may relate to observed aggressiveness and proliferation in G-CIMP-low tumors. From this pilot data, we hypothesize that distal elements regulate the expression of genes in G-CIMP-low which leads to a more aggressive phenotype. These findings corroborate the importance of epigenetics in gliomas and propose that intergenic elements might be driving the G-CIMP-low tumorigenesis.
ACTR-12. PRELIMINARY SAFETY AND EFFICACY OF A PHASE II TRIAL OF 18F-DOPA PET-GUIDED, DOSE-ESCALATED RADIOTHERAPY IN THE TREATMENT OF GLIOBLASTOMA
Authors: Nadia Laack, Deanna Pafundi, S Anderson, Christopher Hunt, Mark Zakhary, Timothy Kaufmann, Hok Seum Wan Chan Tseung, Val Lowe, Elizabeth Yan, Sani Kizilbash, Joon Uhm, Leland Hu, Jann Sarkaria, Paul D Brown, Jan Buckner, Debra Brinkmann
Journal: Neuro-Oncology (2018)

18F-DOPA-PET thresholds reliably delineate areas of high-grade astrocytoma not otherwise recognized with standard MRI and may more accurately identify regions of aggressive, high-density disease. Herein we report the preliminary safety and feasibility data from an ongoing phase II study (MC1374; R01CA178200) evaluating 18F-DOPA-PET guided-dose-escalated radiotherapy for glioblastoma. Newly diagnosed glioblastoma patients without contra-indications to 18F-DOPA-PET are eligible for study enrollment. Target volumes include: CTV51Gy=T1-gadolinium contrast-enhancing (T1-CE) disease, T2 FLAIR signal abnormality, and low-grade 18F-DOPA-PET uptake, +1cm; CTV60Gy=T1-CE and high-grade 18F-DOPA-PET uptake, +1cm; and CTV76Gy=T1-CE and high-grade 18F-DOPA-PET disease without expansion all given in 30 fractions simultaneously. Patients are followed with 18F-DOPA-PET in addition to standard clinical follow-up. Safety stopping rule specifies that after 10 or more patients have been enrolled, if more than 10% experience any of the following adverse events considered to be at least possibly related to treatment, enrollment will be suspended: Grade 3 or 4 irreversible CNS toxicity, Grade 4 non-hematologic, non-CNS toxicity, any Grade 5 toxicity. Futility analysis (and primary study aim) is powered to consider a success to be an MGMT-unmethylated patient who is without progression within 6 months from the time of craniotomy. If 16 or more successes are observed in the first 25 evaluable patients study will continue. 77 patients have been accrued since December 2013 with 68 evaluable for toxicity. Grade 3 CNS necrosis was noted in 3 (4.4%) patients; 2 additional patients developed symptoms that resolved in the subsequent cycle so did not count towards stopping rule. Other grade 3+ toxicities include: 1 patient with pre-existing vision dysfunction had Grade 4 optic nerve dysfunction; 2 Grade 4 hematologic events and 1 Grade 5 event(sepsis) due to temozolamide-induced cytopenias. CONCLUSION: 18F-DOPA-PET -guided dose escalation appears reasonably safe and tolerable in patients with high-grade glioma.
MNGI-31. pFOXM1 PROTEIN EXPRESSION IN WHO GRADE III MENINGIOMAS CORRELATES WITH CDK4/6 GENOTYPE AND TRANSFORMATION HISTORY
Authors: Michael Mooney, Veronica So, An-Chi Tien, Alanna Derogatis, Jennifer Eschbacher, Christine Stephenson, Shwetal Mehta, Nader Sanai
Journal: Neuro-Oncology (2018)

World Health Organization (WHO) Grade III meningiomas are associated with poor clinical outcomes due to high rates of recurrence and limited adjuvant treatment options. The Forkhead Box M1 (FOXM1) transcription factor is a phosphorylation target of CDK4/6 that protects cancer cells from senescence and is upregulated in Grade III meningiomas. We sought to investigate FOXM1 and phosphorylated FOXM1 (pFOXM1) expression in WHO Grade III meningiomas in relation to proliferative index, CDK4/6 cytogenetic profile, and clinical history. We examined 38 tissue specimens from 27 patients with Grade III meningiomas. CDK4, CDK6, and CDKN2A cytogenetic profiles were studied using fluorescence in situ hybridization. FOXM1 and pFOXM1 were identified with immunohistochemistry and quantified using imaging analysis software. pFOXM1 nuclear staining (positive nuclei/mm2) correlated with tumor proliferative index in Grade III meningiomas (mitotic rate > 20, 115.5 vs. mitotic rate < 20, 34.7, P=0.02). Cytogenetic loss of CDK4/6 was associated with significantly decreased pFOXM1 staining (30.8 vs. 111.1, P=0.017). No significant differences in FOXM1 or pFOXM1 staining were observed with gain/amplification of CDK4/6 or with loss of CDKN2A. Grade I/II meningiomas that transformed to Grade III were accompanied by an increase in pFOXM1 staining compared to their de novo counterparts (138.3 vs. 45.9, P < 0.05). pFOXM1 expression correlated with tumor proliferative rate, CDK4/6 cytogenetic status, and prior Grade I/II meningiomas, suggesting a role of FOXM1 signaling in the transformation of lower-grade meningiomas to Grade III lesions. These findings support the potential role for selective CDK4/6 inhibitors as an adjuvant therapy for Grade III meningiomas.
EXTH-67. HIGH-DOSE METFORMIN PLUS TEMOZOLOMIDE SHOWS INCREASED ANTI-TUMOR EFFECTS IN GLIOBLASTOMA IN VITRO AND IN VIVO COMPARED WITH MONOTHERAPY
Authors: Yong-Kil Hong, Seung-Ho Yang
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is one of the most aggressive cancers and the most common primary brain tumor. Although concomitant chemoradiotherapy using temozolomide (TMZ) has been established as the standard therapy, the median survival is approximately 14 months. Metformin, an anti-diabetic agent, has been reported to have anti-tumor effects in various cancers. The purpose of the study is to investigate the efficacy of combined treatment with TMZ and metformin for the treatment of GBM in vitro and in vivo. We investigated the efficacy of combined treatment with TMZ and metformin compared with monotherapy using cell viability and apoptosis assays. A GBM orthotopic mice model was established and treated with metformin, TMZ, and the combination. Survival data were recorded, and tumor specimens were analyzed using western blotting and immunofluorescence. The combination of TMZ and metformin showed higher cytotoxicity than single agents in U87, U251, and A172 cell lines. A combination of high-dose metformin and TMZ showed the highest apoptotic activity. The combination of TMZ and metformin enhanced AMPK phosphorylation and inhibited mTOR phosphorylation and p53 expression. The median survival was 43.6, 55.2, 53.2, 65.2, and 71.3 days in control, metformin (2 mg/25 g/day), TMZ (15 mg/kg/day), combination treatment of low-dose metformin (2 mg/25 g/day) and TMZ (15 mg/kg/day), and combination treatment of high-dose metformin (10 mg/25 g/day) and TMZ (15 mg/kg/day), respectively (p=0.001). Expression of fatty acid synthase (FASN) was significantly decreased in tumor specimens treated with metformin (10 mg/25 g/day) and TMZ (15 mg/kg/day). The combination of metformin and TMZ was superior to monotherapy using metformin or TMZ in terms of cell viability in vitro and survival in vivo. The combination of high-dose metformin and TMZ inhibited FASN expression in an orthotopic model. Inhibition of FASN might be a potential therapeutic target of GBM.
RDNA-04. POTENTIAL MECHANISM OF TEMOZOLOMIDE-MEDIATED RADIO-SENSITIZATION IN MGMT HYPERMETHYLATED GLIOBLASTOMA CELLS
Authors: Gaspar Kitange, Emily Smith, Shiv Gupta, Jann Sarkaria
Journal: Neuro-Oncology (2018)

Temozolomide (TMZ) mediated radio-sensitization is preferentially observed in MGMT hypermethylated glioblastoma (GBM) and is modulated by unknown underlying mechanisms. To gain insight into the potential mechanism of TMZ-induced radio-sensitization, we examined the effect of TMZ pre-exposure on the processing of radiation (RT)-induced double strand breaks (DSBs) in an isogenic model, the U251-vector versus U251-MGMT cells derived by the lentiviral MGMT transduction. Cells were treated with RT (2Gy) alone or after 2 days of pre-exposure to low concentrations of TMZ (20 µM) and survival was evaluated by clonogenic assay and DSBs by western blotting and immunofluorescence based γH2AX and RPA foci. TMZ pre-exposure significantly sensitized RT in U251-vector but not in U251-MGMT cells. In contrast, no significant difference was observed between RT alone and the concurrent RT/TMZ treatment. The radio-sensitization mediated by TMZ pre-exposure in U251-vector cells was accompanied with delayed DSB processing as evidenced by prolonged phosphorylation of KAP1(p-KAP1) and H2AX (γH2AX). Since DNA-PKcs plays a critical role in repair of RT-induced DSBs, we evaluated whether TMZ pre-exposure impacts the phosphorylation of DNA-PKcs in context of RT sensitization. Interestingly, we observed that TMZ alone induced phosphorylation of DNA-PKcs in both U251-vector and U251-MGMT cells and this effect was paradoxically suppressed by RT in time related manner, but in contrast, RT alone significantly increased p-DNA-PKcs. Further experiments confirmed that TMZ induces p-DNA-PKcs in vitro and in vivo and this effect was pharmacologically suppressed by ATR and ATM inhibitors. Importantly, RT-induced DSBs were decorated with p-RPA only in cells pre-exposed to TMZ suggesting single stranded DNA perhaps due to DSB end-resection. Together these results suggest that TMZ-mediated radio-sensitization is due to delayed repair of RT-induced DSBs and the ongoing studies are focused on establishing a link between TMZ-mediated radio-sensitization and TMZ-induced phosphorylation of DNA-PKcs.
EXTH-17. SELECTIVE, NON-COMPETITIVE DRD2/3 ANTAGONISM BY IMIPRIDONE ONC206 IS EFFECTIVE IN TUMORS WITH DOPAMINE RECEPTOR DYSREGULATION
Authors: Varun Vijay Prabhu, Neel Madhukar, Rohinton Tarapore, Mathew Garnett, Ultan McDermott, Cyril Benes, Lakshmi Anantharaman, Neil Charter, Sean Deacon, Alexander VanEngelenburg, Joseph Rucker, Benjamin Doranz, Jessica Rusert, Robert Wechsler-Reya, Olivier Elemento, Martin Stogniew, Wolfgang Oster, Sharon DeMorrow, R Benjamin Free, David Sibley, Joshua Allen
Journal: Neuro-Oncology (2018)

Dopamine receptor D2 (DRD2) is a G protein-coupled receptor that is overexpressed in several cancers and its antagonism has been shown to cause anti-cancer effects. ONC201, an imipridone small molecule, is a DRD2/3 antagonist in Phase II advanced cancer clinical trials. We evaluated the binding target and anti-tumor activity of ONC206, a chemical derivative of ONC201. Experimental GPCR profiling with β-Arrestin recruitment assays revealed that ONC206 selectively antagonizes dopamine receptors DRD2 and DRD3. ONC206 exhibited a Ki of ~320nM for DRD2 with complete specificity across human GPCRs at doses that resulted in complete inhibition. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics that act as competitive and often non-selective antagonists. Shotgun mutagenesis across DRD2 identified 7 residues within and outside of the orthosteric binding site that are critical for ONC206-mediated antagonism. While 6 mutated residues were also critical for ONC201-mediated antagonism, the impact and magnitude of different mutants varied between the two compounds and one of the mutated residues was unique to ONC206 in an allosteric location. In vitro profiling of ONC206 in >1000 GDSC cancer cell lines revealed broad nanomolar efficacy (GI50 <78-889nM). TCGA and tissue microarrays analyses revealed that malignant DRD2 expression was highest in pheochromocytoma, high grade gliomas, neuroblastoma and medulloblastoma with nanomolar in vitro ONC206 sensitivity. A DRD2+/DRD5- RNA expression signature in the GDSC panel predicted significantly enhanced ONC206 sensitivity. ONC206 reduced the viability of normal human fibroblasts at micromolar doses (GI50 > 5µM), suggesting a wide therapeutic window. Robust inhibition of tumor growth was observed with weekly oral ONC206 (50mg/kg) in subcutaneous xenografts of cholangiocarcinoma, a dopamine-secreting bile duct tumor with DRD2 overexpression. Thus, imipridone ONC206 acts as a selective non-competitive DRD2/3 antagonist at nanomolar concentrations with efficacy in tumors with dopamine receptor pathway dysregulation.
TMIC-13. EFFICACY OF RETINOIC ACID IN REVERSING IMMUNE EVASION IN IDH MUTANT GLIOMAS
Authors: Aparna Rao, Xiaoran Zhang, Jason Kim, Youngmi Kim, Eric Holland, Nduka Amankulor
Journal: Neuro-Oncology (2018)

Most diffuse gliomas are characterized by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2). Among its many effects, these mutations drive specific epigenetic programs that result in tumor cell intrinsic resistance to innate lymphoid cells. Here, we define a central role for retinoic acid signaling in mediating immune resistance to innate anti-tumor immunity in IDH mutant tumors. IDH mutations in gliomas suppress retinoic acid signaling through transcriptional repression of Retinol Binding Protein 1 (RBP1), a key chaperone protein in retinoic acid biosynthesis. Loss of retinoic acid signaling results in diminished expression of retinoic-acid-responsive genes, including activating NKG2D ligands ULBP1 and ULBP3 and results in resistance to natural killer (NK cells). We evaluated the efficacy of all-trans retinoic acid (ATRA) as a therapeutic adjuvant for IDH mutant gliomas. In a series of in vitro and in vivo experiments, we assessed the ability of ATRA to increase NKG2D ligand expression in IDH mutant cells, and its ability to increase NK-mediated recognition and killing. We also looked at the impact of ATRA on the tumor immune microenvironment and its underlying mechanisms ATRA treatment led to increased recognition and killing of IDH mutant glioma cells by NK cells, by increasing NKG2D ligand expression. In vivo, ATRA treatment led to significantly slower tumor growth in IDH mutant tumor-bearing mice. Importantly, we made the unexpected finding that restoration of retinoic acid signaling dramatically reshapes the landscape of the immune microenvironment by permitting infiltration of NK cells and CD8 T cells in a manner dependent on the chemokine CCL2. Retinoic acid therapy using ATRA results in marked suppression of IDH mutant glioma tumor growth in an NK cell-dependent fashion in preclinical animal models of glioma. These findings have important therapeutic implications for the treatment of IDH mutant diffuse glioma.
SAT0281 Biologics in sapho syndrome. a systematic review
Authors: D. Daoussis, G. Konstantopoulou, I. Antonopoulos, S.-N. Liossis
Journal: Annals of the Rheumatic Diseases (2018)

Methods: Subjects were AS patients enrolled in the Korean College of Rheumatology Biologics registry KOBIO, Dec 2012 ~).All approved and commonly prescribed TNFi were included in the analysis.Discontinuation was defined as switching or stopping the biologic agent.Kaplan-Meier curve and Cox proportional hazard model were used for further analysis.Reason of TNFi discontinuation was also assessed.Univariate and multivariate analyses were used to identify possible predictors of discontinuation.Results: Data of total of 1005 AS patients were analysed (median follow-up period: 14 months).The mean age of patients was 40.7, and 77.4% were males.The mean disease duration was 7.1 years, HLA-B27 were positive in 82.4%, and 33.2% of patients had lesion(s) of syndesmophytes.Seventy-six percent of patients were first-time biologic users.Discontinuation of TNFi occurred in 24.2% (switching in 9.6%) of patients during follow-up.The drug survival function estimate showed that the adjusted hazard ratio (HR) of golimumab (compared with etancercept) was 0.441 (95% CI 0.277-0.703,p<0.001).The reason of discontinuation was inefficacy (32.6%), adverse events (23.6%), clinical improvement (11.2%), and others (32.6%).A multivariate analysis indicated predictors of discontinuation to be shorter disease duration (HR 0.973, p=0.044), and negative HLA-B27 (HR 1.623, p=0.0093).Conclusions: Our study demonstrates that few AS patients switched to other TNFi during their course of treatment.The drug retention rate of golimumab was higher compared with other agents prescribed in Korean AS patients.
DDIS-12. ONC201: THE FIRST SELECTIVE, NON-COMPETITIVE DRD2/3 ANTAGONIST FOR CLINICAL NEURO-ONCOLOGY
Authors: Varun Vijay Prabhu, Neel Madhukar, Lakshmi Anantharaman, Chidananda Sulli, Edgar Davidson, Sean Deacon, Rohinton Tarapore, Joseph Rucker, Neil Charter, Benjamin Doranz, Wolfgang Oster, Martin Stogniew, Olivier Elemento, R Benjamin Free, David Sibley, Joshua Allen
Journal: Neuro-Oncology (2018)

ONC201 has exhibited preliminary clinical evidence of anti-tumor activity and safety in high grade glioma patients. In this study, we identified and characterized a previously unknown binding target of ONC201. BANDIT – a machine learning-based target identification platform – predicted that ONC201 would bind with high selectivity to the G-protein coupled receptors (GPCRs) dopamine receptor D2(DRD2) and D3 (DRD3). DRD2 is overexpressed in glioma, controls pro-survival mechanisms, and its antagonism causes glioma apoptosis. β-arrestin and cAMP assays determined that ONC201 selectively antagonizes DRD2/3. Consistent with BANDIT and in contrast to antipsychotics that antagonize DRD2, ONC201 did not antagonize other dopamine receptors or other GPCRs. Schild analyses and radioligand competition assays revealed DRD2 antagonism at concentrations consistent with ONC201 anticancer activity. In accordance with superior selectivity, ONC201 exhibited a wider therapeutic window compared to antipsychotics. Combined DRD2/DRD1 inhibition was found to be inferior to DRD2 inhibition alone, suggesting that selectively targeting D2-like receptors yields superior anti-cancer efficacy. ONC201 exhibited a very slow association rate for DRD2 relative to antipsychotics, whereas the dissociation rate was similar to atypical antipsychotics that do not cause extrapyramidal symptoms. Alanine scanning mutagenesis of DRD2 identified 6 residues that are critical for ONC201-mediated antagonism of DRD2 and located in orthosteric and allosteric sites. Molecular docking revealed orthosteric interactions at TM-II and an allosteric interaction at the interface of TM-IV and –V that mediates the DRD2 homodimer interface. These orthosteric and allosteric interactions exhibited predicted affinities associated with the observed competitive and non-competitive effects, respectively, and point mutations at either site increased the Ki of ONC201 in competition assays with radiolabeled methyl-spiperone. In summary, we identify both non-competitive and competitive antagonism of DRD2 by ONC201 that may explain its unique selectivity, safety, and anti-cancer activity in clinical trials as the first compound to target this receptor for oncology.
Determinants of diagnostic delay in chronic thromboembolic pulmonary hypertension: results from the European CTEPH Registry
Authors: Frederikus A. Klok, Stefano Barco, Stavros V. Konstantinides, Philippe Dartevelle, Elie Fadel, David Jenkins, Nick H. Kim, Michael Madani, Hiromi Matsubara, Eckhard Mayer, Joanna Pepke-Zaba, Marion Delcroix, Irene M. Lang
Journal: European Respiratory Journal (2018)

<b>This study identified CTEPH patient characteristics that were predictive of longer diagnostic delay, which in turn was associated with higher pulmonary artery pressures and an increased risk of death</b>http://ow.ly/yCZx30m9TQS
ANGI-02. A CRITICAL ROLE FOR LARG IN RhoC MEDIATED GLIOBLASTOMA CELL INVASION
Authors: Zonghui Ding, Zhiwan Dong, Yuping Yang, Shannon Fortin-Ensign, Hemragul Sabit, Mitsutoshi Nakada, Rosamaria Ruggieri, Marc Symons, Nhan Tran, Joseph Loftus
Journal: Neuro-Oncology (2018)