tbuckley/cabot-search huggingface dataset:
STEM-07. NON-CANONICAL REGULATION OF SOX2 BY THE TRIM26 E3 UBIQUITIN LIGASE IN GLIOBLASTOMA STEM-LIKE CELLS
Authors: Tatenda Mahlokozera, Rukayat Taiwo, Diane Mao, Afshin Salehi, Amit Gujar, Albert Kim
Journal: Neuro-Oncology (2018)

Ubiquitin-dependent signaling is critical for the regulation of glioblastoma stem-like cells (GSCs), a subpopulation of glioblastoma cells responsible for tumor growth and therapy resistance. TRIM26, an E3-ubiquitin ligase with immune-related functions, is highly expressed in glioblastoma tumors compared to normal brain. SOX2 immunoprecipitation followed by mass spectrometry in a patient-derived primary GSC line suggested that TRIM26 interacts with SOX2, a key pluripotency-related transcription factor essential for GSC maintenance. We hypothesized that TRIM26 may play a critical role in GSC maintenance by regulating SOX2. We found that TRIM26 and SOX2 interact directly via the C-terminal PRY-SPRY domain of TRIM26 and the DNA-binding HMG-box of SOX2. Unexpectedly, TRIM26 overexpression resulted in decreased SOX2 polyubiquitination in HEK293 cells. In line with this observation, TRIM26 knockdown in GSCs decreased ambient SOX2 protein levels and stability. Accordingly, SOX2 transcriptional activity, as assessed by a transcriptional reporter, was diminished in the setting of TRIM26 RNA interference (RNAi). Functionally, TRIM26 knockdown reduced GSC self-renewal in vitro and tumorigenicity in vivo in a xenotransplantation mouse model. Mechanistically, TRIM26 competitively reduced SOX2 interaction with WWP2, a bonafide SOX2 E3 ligase in GSCs. Moreover, WWP2 knockdown in GSCs restored SOX2 protein expression in the setting of TRIM26 RNAi. Upstream of TRIM26, we found that tumor-associated macrophage-derived TGFb1 increases TRIM26 expression in GSCs. Together, these results suggest that TRIM26 maintains GSCs by protecting SOX2 from WWP2-mediated ubiquitination and subsequent proteasomal degradation, and further that this pathway may be subject to regulation by the tumor microenvironment.
Abstract 14938: Association Between Survival and Increases in Prehospital Systolic Blood Pressure After Its Nadir in Major Traumatic Brain Injury
Authors: Daniel W Spaite, Chengcheng Hu, Bentley J Bobrow, Duane Sherrill, Vatsal Chikani, Bruce Barnhart, Joshua B Gaither, Kurt R Denninghoff, P. D Adelson, Chad Viscusi, Terry Mullins, Uwe Stolz
Journal: Circulation (2015)

Introduction: Little is known about prehospital EMS blood pressure patterns in TBI and the effect of serial trends in BP during EMS care remains entirely unclear. Using the comprehensive, linked EMS data in the Excellence in Prehospital Injury Care (EPIC) TBI Study (NIH 1R01NS071049; ClinicalTrials.gov NCT01339702), we evaluated the association between mortality and increases in EMS systolic BP (SBP) after the lowest recorded SBP in major TBI cases. Methods: We used the entire EPIC pre-implementation cohort (before TBI guideline implementation; 1/07-3/14) to assess, in detail, a previous preliminary evaluation. All moderate/severe TBI cases (CDC Barell Matrix Type 1) were evaluated [exclusions: age &lt;10, died before ED arrival, SBP &lt;40 or &gt;300, missing SBP (4%)]. Logistic regression was used to determine associations between increases in EMS SBP after the lowest SBP and the probability of death, adjusted for important confounders. Results: Among 14,567 included cases, 7696 (68% male, median age 45) were in the cohort of interest (had an equal or higher SBP recorded subsequent to the lowest). Figures show the probability of death vs the increase after the nadir (and 95% CIs) in 4 cohorts of lowest SBP (40-89; 90-139; 140-159; 160-300). Conclusion: Increases in EMS SBP after the nadir revealed distinct patterns: Hypotension-Mortality drops significantly if SBP increases after the nadir (dramatic improvement with large increases). Normotension-Mortality is slightly reduced with SBP increases and even large increases were not detrimental. Mild HTN-Mortality decreases with modest SBP increases but large increases (&gt;40mmHg) are associated with higher mortality. Severe HTN-Higher mortality with any subsequent increase. The findings in the hypotensive &amp; normotensive cohorts support the concept of restoring/optimizing cerebral perfusion in TBI. This is further supported by the fact that, even with mild HTN, moderate SBP increases do not appear to be detrimental.
ATIM-02. TUMOR TREATING FIELDS IN COMBINATION WITH BEVACIZUMAB IN RECURRENT OR PROGRESSIVE MENINGIOMA IN A PHASE 2 STUDY
Authors: Priya Kumthekar, Tim Kruser, Sean Sachev, Jeffrey Raizer, Sean Grimm, Karen Dixit
Journal: Neuro-Oncology (2018)

For patients with WHO grade II meningioma, the two-year and five-year overall survival is 93% and 73%, respectively. Patients with malignant meningioma (grade III) have significantly worse outcomes, with five-year overall survival rates of 42%. The recurrence rate remains high with overall survival is as low as 3 years after diagnosis. The current treatment for high grade and recurrent meningioma includes maximal safe surgical resection and radiation. Tumor Treating Fields (TTFields) and Bevacizumab (BEV) have been reported to potentially show activity in recurrent and high-grade meningioma. The combination of TTFields and BEV may provide a viable treatment option for patients with recurrent and high grade meningioma. This Phase 2 Simon two-staged, non-randomized, open-label phase II, single arm clinical trial [NCT02847559] will investigate the combination of TTFields and BEV in recurrent or progressive meningioma. The primary endpoint is progression free survival (PFS) at 6 months (PFS-6). Secondary endpoints include overall survival (OS); Tumor Response Rate (TRR), Objective Response Rate (ORR); and Quality of Life (QOL) using FACT-Br questionnaire. Patients (N=27), including those who have failed prior BEV therapy, will receive BEV IV 10 mg/kg over 30–90 minutes on days 1 and 15 of courses 1–4. Beginning on day 1 of course 5, patients may choose to receive bevacizumab IV 15 mg/kg every 3 weeks or remain on the every 2-week schedule. Patients will receive TTFields 200 KHz (1–3 V/cm) daily for at least 18 hours/day. This study is powered to detect a true PFS-6 rate of 20% with 80% probability (80% power) and a true PFS-6 rate of 5% with 90% probability (alpha=0.10). 27 patients were planned to have 24 evaluable patients. To-date 4 patients have been enrolled at the principal site and at least two additional sites are planned to open this year.
QOLP-14. PRELIMINARY EXAMINATION OF CONFIRMED GLIOMA RISK FACTORS AMONG EPENDYMOMA PATIENTS IN THE NEURO-ONCOLOGY BRANCH NATURAL HISTORY STUDY (NOB-NHS) AND RISK AND OUTCOMES STUDY (ROS)
Authors: Alvina Acquaye, Terri Armstrong, Elizabeth Vera, Sonja Crandon, María Fletcher Ruiz, Orwa Aboud, Lisa Boris, Miranda Brown, Nancy Garren, Ming Ji, Jason Levine, Carlos Romo, Jennifer Reyes, Christine Siegel, Jing Wu, Mark Gilbert, Michael Scheurer
Journal: Neuro-Oncology (2018)

The Glioma International Case-Control (GICC) study is the largest study to date examining genetic and environmental risk factors for adult gliomas. Inverse associations have been repeatedly confirmed for allergies, atopic skin diseases, and viral infections. Evaluations of these risk factors specifically ependymoma has not been completed, due to the rarity compared to other glioma types. Therefore, the purpose of this report is evaluating the associations of these confirmed glioma risk factors with ependymomas. Adult ependymoma patients (n=128) enrolled in the NOB-ROS and NHS completed a risk factor questionnaire adapted from the GICC study via a web-based portal. Survey sections related to history of asthma/allergies, common infectious diseases, and regular antihistamine/anti-inflammatory use were examined. Ependymoma patients exposed to these factors were calculated and compared to control (n=1,534) and glioma cases (n=1,339) from a published report (Scheurer, 2011). Odds ratios were calculated for ependymoma using the published controls to compare risk factor effects between ependymoma and glioma cases. The sample was mostly female (62%), median age=45, white (95%), diagnosed with an ependymoma (52%)in the spine (66%). Ependymoma patients were: less likely to have history of asthma/allergy (41%) than controls (66%; OR 0.36, p<0.001); more likely to report regular antihistamine use (23%) than controls (11%; OR 2.38, p<0.001) and all glioma cases combined (p<0.001); and more likely to report regular anti-inflammatory use than all glioma cases combined (p=0.02). Asthma/allergy effects may be more pronounced among ependymoma cases compared to gliomas overall. However, effects of antihistamines and NSAIDs are MUCH worse in ependymoma cases compared to published effects in all cases. This is the first report in adult ependymoma patients exploring risk factors reported in other gliomas and provides preliminary understanding of potential differences in ependymomas. Further analysis should be explored to identify significant areas of concern.
IMMU-20. SINGLE CELL CYTOMICS OF PERIPHERAL BLOOD MONONUCLEAR CELLS REVEALS NEW AVENUES FOR GLIOMA IMMUNOTHERAPY
Authors: Sophie Dusoswa, Jan Verhoeff, Matheus Crommentuijn, Tom Würdinger, David Noske, Yvette Van Kooyk, Juan Garcia-Vallejo
Journal: Neuro-Oncology (2018)

Glioblastoma is the most common primary brain tumor with a dismal prognosis and a lack of effective treatment options after relapse. Despite striking successes that were achieved in the last decade in other types of cancer, evidence of sustainable responses to T cell directed immunotherapy in glioblastoma remains limited. This might be explained by an emerging hypothesis that glioblastomas are cold tumours with poor lymphocyte infiltration. Therefore, some recent efforts have been focused on increasing cytotoxic lymphocyte infiltration. Here we present our workflow for subpopulation frequency, marker expression, and correlation network (INFERENCE) analysis, in this study applied to screen for possible new targets to enhance anti-glioblastoma immune responses. Using high-dimensional, single-cell mass cytometry (CyTOF) we profiled peripheral blood mononuclear cells derived from 160 patients with glioblastoma, lower grade glioma, or metastasis, meningioma and epilepsy as controls. Based on a CyTOF panel composed mainly of lymphocyte markers and check-point inhibition markers we could effectively dissect blood leukocytes into 100 phenotypically separate subsets of CD4 T cells (35 subsets), CD8 T cells (17 subsets), monocytes (12 subsets), NK cells (14 subsets), and B cells (15 subsets), and map their frequencies, phenotypes and correlation statistics. We thereby created an in depth human atlas of peripheral blood mononuclear cells in patients with different types of intracranial tumors. Interestingly, a subset of B cells characterized by high expression of the Interleukin-2 receptor alpha chain (CD25, a typical marker of regulatory T cells) was significantly increased in glioblastoma patients. This immune suppressive B cell subset has previously been associated with enhancing the suppressive effect of regulatory T cells. Further research is warranted to investigate the role of this aberrant B cell subset in the context of glioblastoma and its potential as target for immunotherapy.
NIMG-09. iPROMPT: INTEGRATED PREDICTIVE RADIOGRAPHIC BIOMARKERS OF PROGRESSED HIGH GRADE ASTROCYTIC TUMORS
Authors: Na Tosha Gatson, Joseph Vadakara, Erika Leese, Tierney McGee, T Linda Chi, Gino Mongelluzzo
Journal: Neuro-Oncology (2018)

In 2018 a projected 79,000 persons in the US will be diagnosed with a primary brain tumor. Glioblastoma (GBM) is the deadliest and most common of these tumors in adults with overall survival ~15 mos and >93% of patients deceased by 5-years. Disease progression is inevitable, and effective second-line therapies are few. Delays in identifying progressed GBM risks neurologic decline and increased tumor mutations that potentially renders treatment less-effective. Reliable brain tumor imaging can be ambiguous to distinguish true progression from treatment effect. Furthermore, inaccurate identification of tumor progression might result in continuation of ineffective treatment or premature discontinuation of effective therapies. This is an active topic in neuro-oncology as it applies to patient care and standardization of imaging techniques. Improved tumor imaging surveillance tools that supplement current standards and allow earlier detection of progression can improve clinician confidence and patient outcomes. This study collected 468 WHO grade IV astrocytomas with gross-total-resection within our institution between 2006 and 2017 to evaluate changes in T2/FLAIR signal intensity, diffusion restriction, and contrast enhancement both in and around the resection cavity to determine earliest indicators of tumor progression. Early data release of this ongoing retrospective study reveals encouraging findings that support a novel combination of radiographic biomarkers associated with GBM progression using standard brain tumor imaging. A feasibility study including 47 cases, thus far, support previously reported signal intensity changes within the resection cavity as well as specific phenomena that have not been previously described, such as FLAIR migration and signal coring. The proposed technique does not require advanced brain tumor imaging and can therefore be broadly employed and standardized in clinical practice. With further validation, this novel combination of imaging features that might serve to supplement existing response criteria.
Abstract 20637: Changes in Gene Expression Profile of Porcine Myocardium After Repetitive Ischemia/Reperfusion
Authors: Noemi Pavo, Dominika Macejovska, Katrin Zlabinger, Dietmar Pils, Gerald Maurer, Maximilian Emmert, Simon Hoerstrup, Mariann Gyöngyösi
Journal: Circulation (2014)

Introduction: Gene expression profile of the myocardium after repetitive ischemia/reperfusion (I/R) was analyzed under experimental conditions. Hypothesis: This animal model simulates human pre-infarction angina pectoris. Methods: Domestic pigs (n=20) underwent closed chest repetitive (3x5min cycle) I/R by percutaneous balloon occlusion/deflation of the mid LAD. Sham intervention was performed in controls. After 5h and 24h, myocardial samples were harvested from the entire heart (totally 56 samples equally distributed) from the apex to the heart basis localized by using anatomical landmarks. Next generation sequencing (NGS) of the ischemic, border zone and remote myocardium was performed to identify crucial pathways involved in myocardial protection. The hypoxia inducible factor-1 (HIF-1alpha), Caspase-3, GATA4 and myocyte enhancer factor 2C (MEFC2) gene expression levels were analysed using quantitative real-time PCR (rtPCR) and displayed in 2D polar maps. Results: NGS resulted in significant differences...
<i>Notes from the Field: Cronobacter sakazakii</i> Meningitis in a Full-Term Neonate Fed Exclusively with Breast Milk — Indiana, 2018
Authors: Madhura Sundararajan, Leslie A. Enane, Laurie A. Kidwell, Ryan Gentry, Stanley Danao, Samina Bhumbra, Christopher Lehmann, Megan Teachout, Jamie Yeadon-Fagbohun, Peter Krombach, Betsy Schroeder, Haley Martin, Jonathan Winkjer, Thomas Waltz, Jonathan Strysko, Jennifer R. Cope
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
PDTM-22. TARGETING A NOVEL METABOLIC DEFECT IN PPM1D-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Nathan Fons, Ranjini Sundaram, Greg Breuer, Charles Brenner, Ranjit Bindra
Journal: Neuro-Oncology (2018)

Somatic truncating mutations within the oncogenic phosphatase PPM1D, have been identified in diffuse intrinsic pontine glioma (DIPG) and other high grade pediatric brain tumors. These stabilizing mutations result in an overabundance of the mutant protein within tumor cells, and inactivation of important DNA damage response (DDR) and cell cycle checkpoint targets. Despite our current understanding of these mutations, there exists no viable therapeutically viable strategy for the treatment of PPM1D-mutant tumors. Therefore, we sought to further explore the oncogenic potential of these truncating mutations, and to identify selective inhibitors of mutant DIPGs. Using isogenic astrocyte pairs with containing engineered-PPM1D mutations, we characterized the phenotypic effects of these genetic alterations on DDR and DNA repair processes. We identified numerous DNA repair defects that likely can be exploited for a therapeutic gain, including accelerated gH2AX dephosphorylation, which correlated with despite an intact 53BP1 DNA damage response (DDR), which correlated with intrinsic radiosensitivity. We then performed a small molecule screen with inhibitors of DDR-related proteins to identify novel synthetic lethal pathways in PPM1D-mutant DIPGs. These studies revealed an unexpected, clinically actionable target in PPM1D-mutant cells, involved in global cellular metabolism. This induced sensitivity was detected using multiple drugs targeting the same pathway, and was exquisitely selective, with a 104 –fold difference in sensitivity between mutant and wild type cells. Further, upon testing these compounds against patient-derived, PPM1D-mutant DIPG neurospheres, we again found remarkable levels of sensitivity, demonstrating their effects in relevant preclinical models. We will present the mechanistic basis for this described synthetic lethality, which implicates key epigenetic alterations and gene expression changes, ultimately resulting in the described metabolic defect. Overall, our novel discovery provides exciting new insights into the biology of PPM1D mutations and the treatment of these devastating pediatric diseases.
Regulation of prostate cancer sensitivity to apoptosis by CDDP by downregulation of XIAP and Bcl-xL expression via inhibition of constitutive NF-κB activity
Authors: Sara Huerta-Yepez, Mario Vega, Fumiya Hongo, Ali R. Jazirehi, Hermes Garban, Yoichi Mizutani, Benjamin Bonavida
Journal: Cancer Research (2004)

4826  Prostate cancer patients develop chemoresistance following initial treatment. Several studies have been addressed to determine the underlying mechanisms of resistance and included the development of the MDR phenotype, dysregulation of the apoptotic signaling pathways, etc. We and others have demonstrated in CaP cell lines that NF-κB is constitutively activated and regulates survival and growth of the tumor cells. We have demonstrated that PC-3 and DU-145 synthesize and secrete cytokines such as TNF-α and IL-6 that regulate NF-κB activity via an autocrine paracrine pathway. Further, these cytokines were found to regulate drug resistance. Therefore, we hypothesized that NF-κB may regulate drugs-induced apoptosis via dysregulation of the apoptotic signaling pathways and hence inhibition of NF-κB may chemosensitize the cells. The objective of this study was to test this hypothesis and delineate the gene products that are transcriptionally regulated by NF-κB and contribute to chemoresistance. We demonstrate that treatment of PC-3 cells with NF-κB inhibitors sensitized the cells to CDDP-induced apoptosis and synergy was achieved. Further, inhibition of NF-κB by a nitric oxide donor (DETANONOate), via the S-nitrosylation of p50, also resulted in chemosenstization. The effect of NF-κB on the apoptosis signaling pathways, as determined by western, revealed that there was selective downregulation of the anti-apoptotic XIAP and Bcl-xL gene products following inhibition of NF-κB. The role of these proteins in chemosensitization was corroborated by the use of specific inhibitors. These findings suggest that tumor cells develop a self-contained mechanism to resist drug-induced apoptosis by tumor-derived autocrine/paracrine factors which activate NF-κB and secure cell growth and survival. Further, the present findings suggest that NF-κB, XIAP and Bcl-xL are targets for intervention in the reversal of drug resistance. Supported by a grant from the Department of Defense (US Army DAMD 17-02-1-0023), Jonsson Comprehensive Cancer Center (MV, AJ), UCLA SPORE in Prostate Cancer (P50 CA92131-01A1), Fogarty (SH-Y, MV, HG), and UC MEXUS (SH-Y).
Abstract 17083: Clinical Scenario Classification Predicts Future Clinical Outcome in Patients With Heart Failure and Reduced Ejection Fraction
Authors: Jin Komuro, Yuji Nagatomo, Mayuko Yagawa, Keitaro Mahara, Ayumi Goda, Yasumori Sujino, Atsushi Mizuno, Takashi Kohno, Shun Kohsaka, Mitsuaki Isobe, Tsutomu Yoshikawa
Journal: Circulation (2017)

Introduction: Clinical Scenario (CS) classification based on blood pressure recordings has been widely utilized to guide the treatment of acute decompensated heart failure (ADHF). However, the clin...
ATIM-31. PHASE I STUDY OF TUMOR TREATMENT FIELDS AND A PERSONALIZED MUTATION-DERIVED TUMOR VACCINE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Adilia Hormigo, Alex Rubinsteyn, Julia Kodysh, Raymund Yong, Constantinos Hadjipanayis, Joshua Bederson, Nadejda Tsankova, Jane Houldsworth, Nina Bhardwaj
Journal: Neuro-Oncology (2018)

The tumor microenvironment of a glioblastoma is highly immunosuppressive. Overcoming this immunosuppressive activity seems imperative to a successful treatment. Like other cancers, glioblastoma is capable of generating tumor-specific peptides that can be recognized by the immune system, providing a specific target for antitumor therapy. Glioma vaccines including tumor lysate pulsed dendritic cell-based immunotherapy have proven safe and potentially of clinical value, suggesting that dead cells can confer tumor associated antigens for processing and presentation. Use of TTFields in newly diagnosed glioblastoma increases progression-free survival and overall survival. Among several mechanisms of action, TTFields induces an immunogenic cell death. Therefore, we combined this modality treatment with the standard of care and a personalized vaccine for newly diagnosed glioblastoma with the expectation of improved outcome for the patients. RNA and DNA are extracted from tumor specimens and blood and whole exome sequence and mRNASeq is performed. HLA typing is obtained for each patient. Mutation-derived tumor antigens are identified using computational predictions and ranked according to both predicted HLA binding affinity and expression. A maximum of 10 peptides is selected for each patient vaccine. The vaccine is administered subcutaneously using Poly-ICLC as adjuvant during Temozolomide treatment after radiotherapy with concurrent Temozolomide. We are reporting on the initial safety data for patients who received the mutation-derived tumor antigen vaccine without the use of the TTFields. We have encountered not only novel mutated tumor antigens but also well known driver mutations that are predicted to be immunogenic despite a low mutation load in the GBM patients. The trial is feasible and the vaccine seems well tolerated without unexpected adverse events.