tbuckley/cabot-search huggingface dataset:
EXTH-08. MESENCHYMAL GLIOBLASTOMA CONSTITUTES A MAJOR ceRNA SIGNATURE IN THE TGF-PATHWAY
Authors: Qixue Wang, Yunfei Wang, Chuan Fang, Yanli Tan, Chunsheng Kang
Journal: Neuro-Oncology (2018)

ceRNA networks play important roles in post-transcriptional regulation. Their dysregulation is common in cancer. However, ceRNA signatures are barely examined for mesenchymal glioblastoma characteristic of invasive and aggressive phenotypes. Here, we investigated the mRNAs in ceRNA networks (micNET) of glioblastoma by constructing a GBM ceRNA network, followed by being integrated with STRING protein interaction network. We report that six micNETs (TGFBR2, RUNX1, PPARG, ACSL1, GIT2 and RAP1B) signify mesenchymal GBM across multiple datasets. Patients with highly expressed micNET markers have poor response to TMZ chemotherapy. Mechanistically, the ceRNA interaction were identified between micNETs and miR181s family members. The inhibitor of TGFBR2, LY2109761, demonstrated tumor-suppressive effect on both primary cultured cell and PDX intracranial model. Thereby, the micNETs provide a promising translational significance in diagnosis of mesenchymal GBM as well as novel therapeutic targets. In conclusion, our study revealed that the ceRNA signature of mesenchymal glioblastoma was enriched in the TGF-β pathway and characterized this subtype in the mRNA-miRNA dimension. We identified that key micNETs signatures could be used to diagnose mesenchymal GBM and discovered that the TGF-β pathway is a potential therapeutic target for mesenchymal glioblastoma.
Publisher Correction: Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis
Authors: Erik Ellwardt, Gautam Pramanik, Dirk Luchtman, Tanja Novkovic, Eduardo Rosales Jubal, Johannes Vogt, Isabelle Arnoux, Christina Francisca Vogelaar, Shibajee Mandal, Melanie Schmalz, Zeke Barger, Inigo Ruiz de Azua, Tanja Kuhlmann, Beat Lutz, Thomas Mittmann, Stefan Bittner, Frauke Zipp, Albrecht Stroh
Journal: Nature Neuroscience (2018)
Abstract 16687: A Genetic Contribution to Postoperative Complete Heart Block Following Congenital Heart Surgery
Authors: Andrew H Smith, English C Flack, Kimberly Crum, Prince J Kannankeril
Journal: Circulation (2015)

Background: A familial variant of complete heart block (CHB) is described in association with a substitution mutation in Connexin-40 (GJA5 Q58L) resulting in impaired gap junction formation. We sought to identify genomic predictors that may independently predispose children to the development of early postoperative complete atrioventricular (AV) block following congenital heart surgery. Methods: Subjects undergoing congenital heart surgery at our institution were consecutively recruited and enrolled from September 2007 through December 2014. In addition to DNA, demographic and perioperative clinical data were obtained from all subjects. Results: Over the course of the study period, there were 1466 subjects enrolled who underwent 1986 operative procedures; DNA was available for analysis in 1756 cases (1424 subjects). The incidence of at least one episode of postoperative complete AV block was 3.7% (n=65). Genotyping of the common missense polymorphism rs10465885 in GJA5 among subjects yielded allele frequencies in Hardy Weinberg equilibrium (p=0.73), and analysis demonstrated a gene-dose effect association between T allele presence and incidence of postoperative complete AV block (linear by linear association, p=0.009). Multivariate logistic regression analysis demonstrates that TT homozygosity is associated with a two-fold increased odds of new onset complete AV block (OR 2.1, 95%CI 1.2-3.5, p=0.006), independent of other significant univariate predictors including patient weight (p&lt;0.001), operative procedure including closure of a ventricular septal defect (p&lt;0.001), chromosomal anomaly (p=0.016), cross clamp time (p&lt;0.001), ionized calcium and serum lactate on admission (both p&lt;0.001), inotrope use on admission (p&lt;0.001), and preoperative digoxin administration (p&lt;0.001). Conclusions: A common missense single nucleotide polymorphism within a gene encoding Connexin-40 is associated with the development of early postoperative complete heart block, independent of established risk factors. A refined understanding of genotype-phenotype relationships may serve to guide early postoperative care following congenital heart surgery.
Abstract 16384: Molecular Genetics of Familial Abdominal Aortic Aneurysms; a Focus on SLC2A10
Authors: J Burger, A IJpma, D Heijsman, H Liu, P van Heijningen, T ten Hagen, M Wessels, H Bruggenwirth, H Verhagen, R Kanaar, D Majoor-Krakauer, I van der Pluijm, J Essers
Journal: Circulation (2017)

Introduction: Abdominal aortic aneurysm (AAA) is an age-related life threatening disease, familial in about 25% of the cases. At least 3% of AAA can be explained by defects in thoracic aneurysm (TA...
Prevalence of Arthritis Among Adults with Prediabetes and Arthritis-Specific Barriers to Important Interventions for Prediabetes — United States, 2009–2016
Authors: Michelle Sandoval-Rosario, Babak Michael Nayeri, Addey Rascon, Michael Boring, Teresa Aseret-Manygoats, Charles G. Helmick, Louise B. Murphy, Jennifer M. Hootman, Giuseppina Imperatore, Kamil E. Barbour
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

An estimated 54.4 million U.S. adults have doctor-diagnosed arthritis (arthritis), and this number is projected to rise to 78.4 million by 2040 (1,2). Physical inactivity and obesity are two factors associated with an increased risk for developing type 2 diabetes,* and arthritis has been determined to be a barrier to physical activity among adults with obesity (3). The prevalence of arthritis among the 33.9% (estimated 84 million)† of U.S. adults with prediabetes and how these conditions are related to physical inactivity and obesity are unknown. To examine the relationships among arthritis, prediabetes, physical inactivity, and obesity, CDC analyzed combined data from the 2009-2016 National Health and Nutrition Examination Surveys (NHANES). Overall, the unadjusted prevalence of arthritis among adults with prediabetes was 32.0% (26 million). Among adults with both arthritis and prediabetes, the unadjusted prevalences of leisure-time physical inactivity and obesity were 56.5% (95% confidence intervals [CIs] = 51.3-61.5) and 50.1% (CI = 46.5-53.6), respectively. Approximately half of adults with both prediabetes and arthritis are either physically inactive or have obesity, further increasing their risk for type 2 diabetes. Health care and public health professionals can address arthritis-specific barriers§ to physical activity by promoting evidence-based physical activity interventions.¶ Furthermore, weight loss and physical activity promoted though the National Diabetes Prevention Program can reduce the risk for type 2 diabetes and reduce pain from arthritis.
Upregulation of the orphan nuclear receptor NR4A3 in drug-induced apoptosis of tumor cells and its relationship to mitochondrial VDAC1
Authors: Kala Ramaseshan, Patrick Tan, Shazib Pervaiz
Journal: Cancer Research (2007)

3597   Mitochondria play a critical role in the execution of tumor cells following drug exposure. We have previously reported the apoptosis inducing activity of the novel small molecule, C1 (merodantoin), a photoproduct of merocyanine 540. This includes fragmentation of DNA, activation of caspases 2, 3, and 9, translocation of Bax to the mitochondria and the reciprocal egress of cytochrome C to the cytosol. In addition, exposure of tumor cells to C1 results in an early increase in intracellular hydrogen peroxide production and cytosolic acidification, thus creating an environment conducive for death execution. To further understand the signaling circuitry and upstream modulators of C1-induced apoptosis in tumor cells, here we used a high throughput microarray analysis to pick out genes that were up- or down-regulated upon C1 treatment. We identified among other genes, NR4A3, which encodes an orphan nuclear receptor, transcriptionally upregulated within 1-2 hours of treatment. These data were then validated using NR4A3 specific primers by Real time PCR. Furthermore, to identify partners in the signal transduction pathway mediated by NR4A3 we looked at the co-expression neighborhood of NR4A3 in cancer datasets and found that it includes among other genes, voltage dependent anion channel 1 (VDAC1), a mitochondrial outer membrane protein involved in mitochondria-mediated apoptosis. Of note, VDAC1 transcript and total protein levels did not change upon drug treatment, however a significantly higher mitochondrial VDAC1 was detected in the mitochondria following 12 hours incubation with the compound. To further gain insight into the relationship between NR4A3 expression and mitochondrial localization of VDAC1, the expression of NR4A3 was silenced by siRNA. Interestingly, silencing NR4A3 blocked C1-induced mitochondrial translocation to or expression of VDAC1. These data suggest that NR4A3 could modulate the apoptotic response by impacting on translocation of critical proteins to mitochondria, which are involved in apoptotic signaling. In summary, here we report a novel role for NR4A3 in drug-induced apoptosis, indicating specific involvement of mitochondria.
Author Correction: Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors
Authors: Huipeng Li, Elise T Courtois, Debarka Sengupta, Yuliana Tan, Kok Hao Chen, Jolene Jie Lin Goh, Say Li Kong, Clarinda Chua, Lim Kiat Hon, Wah Siew Tan, Mark Wong, Igor Cima, Min-Han Tan, Lawrence J K Wee, Axel M Hillmer, Iain Beehuat Tan, Paul Robson, Shyam Prabhakar
Journal: Nature Genetics (2018)
Correlation of clonogenic cancer stem cell (CSC) growth with clinical outcomes in multiple myeloma (MM) patients undergoing treatment with high dose cyclophosphamide (Cy) and rituximab
Authors: Carol Huff, Qiuju Wang, Kathryn Rogers, Miah Jung, Javier Bolanos-Meade, Ivan Borrello, Richard Jones, William Matsui
Journal: Cancer Research (2008)

LB-87  CSC have been identified in many tumor types, but the clinical significance remains unclear. Results from our group indicate that MM is comprised of 2 cellular compartments: terminally differentiated plasma cells (PC) and rare clonogenic MM stem cells resembling memory B cells. We also found that MM-CSC are relatively resistant to anti-MM agents when compared to MM-PC in vitro (Matsui et al Cancer Res 2008). Thus, we conducted a phase II trial with a combination of agents targeting both cellular compartments: Cy (50 mg/kg/day x 4 days) for MM-PC and rituximab (375 mg/m2 x 2 doses prior to Cy then weekly x 4 following count recovery and at 3, 6, 9, 12 mos post-Cy in absence of progression) for MM-CSC. Patients (pts) with primary refractory disease, high risk 1st remission (defined as B2M > 5.0 or del 13 by FISH or cytogenetics), or relapsed disease responding to salvage treatment were eligible. 21 pts were enrolled and treated. Median age was 58 (range 42-70). 62% (13/21) of pts had Durie Salmon Stage III and 50% (7/14) were ISS Stage 3 based on available data. Median number of prior treatments was 1 (range 1-4). At time of trial entry, 15 were considered high risk 1st remission, 1 primary refractory and 5 > PR2. There were no treatment-related deaths, although 3/21 pts have died due to disease progression. Based on uniform response criteria, the following responses were seen: 1 CR, 2 very good PR, 14 PR (or continued PR), 4 progressive disease. At present, 3 pts remain progression-free (139-616 days after Cy). Median time to progression was 213 days (range 60-651). Median duration of response was 194 days (range 60-638). Median overall survival has not been reached with median follow-up of 494 (range 119-1014) days. Correlative studies quantified changes in MM-CSC during and up to 1 yr post-Cy. Complete data is available for 16/21 pts. In the majority, the relative frequency of clonogenic MM-CSC decreased by an average of 44 (range 5-95) %, immediately after treatment. Clonogenic MM-CSC returned to pre-treatment levels within 12 mos in 11 pts who demonstrated median progression-free survival (PFS) of 185 (range 60-280) days. In contrast, pts (n=5) with a persistent decrease in clonogenic MM-CSC at 12 mos had a significantly prolonged PFS of 564 (range 431-651) days (p
ACTR-03. A FEASIBILITY TRIAL OF THE MODIFIED ATKINS DIET AND BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA
Authors: Lisa Rogers, Sarah Rolfe, Karen Devine, David Peereboom, Michelle Palcsik, Mohamed Hamza, Ann Riehl, Marge Marsey, Nathan A Berger, Joseph Gibbons, Jill Barnholtz-Sloan, Andrew Sloan, Curt Tatsuoka
Journal: Neuro-Oncology (2018)

We report results of a feasibility trial of the modified Atkins diet (MAD), a form of ketogenic diet (KD), combined with bevacizumab (Bev) for recurrent GBM. The rationale for a KD to treat GBM includes the reduction of glucose availability to this highly glycolytic tumor, reduction of a variety of GBM growth signaling pathways, and increase in tumor-reactive immune responses. Clinical and laboratory data indicate the combination of KD and Bev is more effective than either treatment alone (Reiger et al 2014). Because adherence to the MAD and Bev in patients with GBM cannot be predicted, we performed a measure of treatment compliance before proceeding to an efficacy trial. Feasibility study in 12 Bev naïve recurrent GBM patients. Bev was administered in standard doses biweekly. The primary objective was to document compliance with MAD in at least 60% of the patients (7/12) at least 80% of the time at 12 weeks. Secondary objectives included adverse events, tumor response, PFS, OS. Monitoring of MAD biologic effects included serum glucose and urine ketones daily and serum B-hydroxybutyrate biweekly. Compliance was determined by review of daily food diary and ketone levels. 8/12 patients completed the trial at 12 weeks and all were compliant with diet and all achieved ketosis. One additional patient continues on study at 48 days. Three patients were removed from study: grade 3 hypertension related to Bev, grade 3 seizures related to tumor, tumor progression at 71 days. CONCLUSION: We document the feasibility of the MAD and Bev in recurrent GBM. We will present correlations of treatment outcome with serum levels of ketosis, glucose, insulin, amino acids and with tumor MCT4 expression and IDH1 mutation status. Funding: Ohio Clinical Trials Collaborative, Blast GBM, Sally S. Morley Memorial Glioblastoma Treatment Fund, Nutricia
A Quadruplet Regimen Comprising Carfilzomib, Cyclophosphamide, Lenalidomide, Dexamethasone (KCRD) Vs an Immunomodulatory Agent Containing Triplet (CTD/CRD) Induction Therapy Prior to Autologous Stem Cell Transplant: Results of the Myeloma XI Study
Authors: Graham H Jackson, Faith E. Davies, Charlotte Pawlyn, David Cairns, Alina Striha, Anna Hockaday, Corinne Collett, John R Jones, Bhuvan Kishore, Mamta Garg, Catherine Williams, Kamaraj Karunanithi, Jindriska Lindsay, Matthew Jenner, Gordon Cook, Nigel H. Russell, Martin Kaiser, Mark T Drayson, Roger G. Owen, Walter M Gregory, Gareth Morgan
Journal: Blood (2018)
Abstract 13379: The Prognostic Value of Pulse Oximetry Plethysmographic Waveform During CPR
Authors: Jun Xu, Chen Li, Huadong Zhu, Xuezhong Yu
Journal: Circulation (2015)

Introduction: A facile, early predictor of the outcome of resuscitation is needed. Pulse oximetry, which noninvasively detects the blood flow of peripheral tissue, has achieved widespread clinical use. We noticed that the better the quality of CPR was, the better the appearance of pulse oximetry plethysmographic waveform (POP) was. Hypothesis: We assessed the hypothesis that the amplitude of POP (Amp) and the area under the curve of POP (AUC) could be utilised as a tool to predict the outcome of resuscitation. Methods: 617 cardiac arrest patients from 14 hospital in 10 cities were enrolled in the study and retrospectively assigned to two groups: ROSC group and non-ROSC group. Estimation of prognosis of cardiac arrested patients through the analysis of change of POP parameters during CPR. Results: POP parameters in chest compressions stage [Amp (111.0 (66.0,210.5) vs 41.0 (23.0,119.8)) PVA, AUC (3243.5±30.8 vs 2334.0 (1827.0,3229.0)) PVPG (Figure 1)] and PETCO2 [(23.1±4.0 vs 13.0(8.0,23.0)) mmHg (Figure 2)] were statistically different between ROSC group and non-ROSC group (P &lt; 0.01). Cut-off values for ROSC in CPR patients were shown in Table 1. Conclusions: In conclusion, POP parameters could help predict the prognosis of the patients during CPR. The prognostic value of POP parameters was non inferiority to PETCO2, and this method was noninvasive, safe, economy.
PDTM-20. ELUCIDATING MOLECULAR PATHOGENIC MECHANISMS OF THE HISTONE H3.3 G34R MUTATION IN PEDIATRIC HIGH-GRADE GLIOMAS (HGGs)
Authors: Santiago Haase, María Belén Garcia-Fabiani, Felipe Nunez, Padma Kadiyala, Fernando Nunez, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2018)

High-grade glioma (HGG) is the most common and lethal type of primary brain tumor in humans, remaining essentially incurable; 16% of pediatric and young adult HGGs in cerebral hemispheres encode Gly34Arg/Val (G34R/V) substitutions in the histone variant H3.3. It was shown that H3.3G34R/V leads to a local downregulation of H3K36 trimethylation at specific genes’ loci. Although K36me3 has been associated to various mechanisms including DNA repair, gene expression and chromatin homeostasis, the specific mechanisms by which H3.3G34R/V drive malignancy of HGGs remain largely unknown. We developed a mouse model of H3.3-G34R HGG by transfecting a transposase-expressing plasmid along with transposable cassettes to drive the expression of H3.3G34R, shRNAs against p53 and Atrx (genes whose mutations co-segregate with H3.3G34R in HGGs) and NRAS, into neonatal mice. We compared H3.3G34R, NRAS, shp53, shAtrx, tumors (NPAH) with H3.3 wild type, shp53, shATRX, tumors (NPA), and observed an increased median survival in NPAH tumors compared to NPA. To further address the role of G34R mutation in oncogenesis we integrated H3.3G34R/V into SJ-GBM2, an H3.3 wild type pediatric HGG cell culture. Wild type SJ-GBM2 cells formed tumors when intracranially injected into NSG mice, but SJ-GBM2-H3.3G34R cells did not. We observed that SJ-GBM2-H3.3G34R undergo a series of molecular changes: i.e., neural cells’ dedifferentiation, evidenced by decreased levels of Olig1, Olig2 and GFAP; epigenetic reprogramming evidenced by global changes in H3K36 acetylation and H3K27 acetylation; a switch in DNA repair pathways, from homologous recombination to non-homologous end joining; and upregulation of DLX6, a transcription factor with roles in forebrain and craniofacial development. Our results indicate that H3.3G34R/V mutations may drive tumorogenesis by maintaining neural cells’ undeferenciation, altering the DNA repair pathway choice and inducing epigenetic changes, with potential consequences in mutational burden and genomic stability. These characteristics could be exploited to design novel therapies.
ACTR-66. BEVACIZUMAB THERAPY FOR THE TREATMENT OF ADULT GLIOBLASTOMA: SYSTEMATIC REVIEW &amp; META-ANALYSIS
Authors: Nagham Kaka, Karim Hafazalla, Sunit Das
Journal: Neuro-Oncology (2018)

INTRODUCTION: Glioblastoma is the most common high-grade primary brain tumor in adults. Standard multi-modality treatment of glioblastoma often results in transient tumor control, but inevitably gives way to disease progression. The need for other therapeutic avenues led to interest in the anti-angiogenic therapy, namely bevacizumab, as a treatment for glioblastoma. We sought to determine the efficacy of bevacizumab as a treatment for glioblastoma. We conducted a literature search using the PubMed database and Google Scholar to identify randomized controlled trials (RCTs) since 2014 investigating the safety and efficacy of bevacizumab in the treatment of adult patients (18 years and older) with both newly diagnosed and recurrent glioblastoma. Only Level I data that reported progression-free survival (PFS) and overall survival (OS) were included for analysis. We identified 14 studies that met our criteria, reporting on a total of 3,192 patients. Our preliminary analysis finds that treatment with bevacizumab consistently prolongs PFS with a correspondent decrease in PFS hazard ratio (HR) for treatment groups that include bevacizumab versus those that do not. Bevacizumab had no significant effect on OS in patients with newly diagnosed or recurrent glioblastoma. Seven studies reported on MGMT status: four studies found that patients with methylated MGMT status had a consistently longer PFS and OS, corresponding with significantly lower HR for both variables, when compared to unmethylated groups. Our preliminary findings suggest that bevacizumab therapy is associated with a longer PFS in adult patients with glioblastoma, however, bevacizumab had an inconsistent effect on OS in this patient population. The differential response to bevacizumab in relation to MGMT methylation status and molecular subtype requires further analysis.
PDTM-39. HISTONE H3 MUTATION EFFECTS ON CHROMATIN STRUCTURE AND REGULATION OF GENE TRANSCRIPTION IN PEDIATRIC GLIOMA
Authors: Amanda Saratsis, Tina Huang, Andrea Piunti, Patrick A. Ozark, Elizabeth Bartom, Stacy Marshall, Rintaro Hashizume, C David James, Ali Shilatifard
Journal: Neuro-Oncology (2018)

Pediatric high-grade glioma (HGG), including H3K27M diffuse midline glioma, has the highest mortality of pediatric solid tumors. Recurrent Histone H3 mutations result in methionine for lysine substitution (H3K27M) in 80% of diffuse midline gliomas, or valine for glycine/arginine substitution (G34V/R) in 50% of hemispheric HGGs. These mutations alter chromatin structure and are associated with distinct patterns of gene expression and poorer response to therapy. To elucidate the mechanism by which these mutations affect chromatin function, we characterized genomic deposition of Histone H3 proteoforms in a large cohort of rare pediatric glioma cell lines. H3K27M DIPG (n=6), H3G34V (n=1) and wild-type pediatric high-grade glioma cells (n=2), neural stem cells (n=1) and astrocytes (n=1) were analyzed for genomic deposition patterns of H3.3, H3K27M, H3G34V, H3K27me3, H3K27Ac, H4Kme1, and H4Kme3. Extracted chromatins were sonicated to produce DNA fragments for ChIP. RNA was extracted for whole transcriptome profiling. DNA/RNA libraries were prepared using the KAPA HTP Library Preparation Kit and sequenced (ChIP-and RNA-Seq, Illumina NextSeq 500). Genomic enrichments and gene expressions were determined, quantified, and analyzed for biological relevance. Distinct genomic enrichment of H3 proteoforms was observed between mutant and wild type cell lines, corresponding with respective gene expression levels. Differential co-localization of H3 post-translational marks with mutant vs. wild type H3 protein was also observed, consistent with our prior description of mutant heterotypic nucleosomes. Location of specific marks (promoter, gene body) suggests altered transcription factor recruitment and function may result in observed patterns of gene expression. We present the largest known epigenetic analysis of pediatric glioma cell lines to date, indicating distinct patterns of Histone H3 enrichment and gene expression in H3K27M and H3G34V/R mutant lines. These data provide insight into the mechanisms by which H3 mutations impact pediatric glioma biology, which may inform novel therapeutic approaches.