tbuckley/cabot-search huggingface dataset:
CSIG-47. TRIM24 IS AN ONCOGENIC TRANSCRIPTIONAL CO-ACTIVATOR OF STAT3 IN GLIOBLASTOMA
Authors: Haizhong Feng
Journal: Neuro-Oncology (2018)

Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. Here, we determine that non-canonical histone signature acetylated H3 lysine 23 (H3K23ac)-binding protein tripartite motif-containing 24 (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. In multiple glioma cell lines and patient-derived glioma stem cells (GSCs), EGFR signaling promotes H3K23 acetylation and association with TRIM24. Consequently, TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Additionally, H3K23 acetylation also recruits TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Moreover, lysine acetyltransferase KAT6A, a chromatin regulator which contributes to histone modification and cancer, is upregulated by EGFR activation and acetylates H3K23 in gliomas. KAT6A expression is associated with GBM patient survival and upregulated by EGFR signaling. KAT6A silencing suppressed cell proliferation, cell migration, colony formation and tumor development in an orthotopic mouse xenograft model system. Taken together, our findings uncover TRIM24 functions as an epigentic oncogene in glioblastoma and suggest TRIM24 as a potential therapeutic target for GBM that are associated with EGFR activation.
Abstract 11509: QT Rate Dependence is Reduced in Brugada Syndrome Independent of Genotypic Status
Authors: Tomas Robyns, Rik Willems, Joris Ector, Christophe Garweg, Cuno Kuiperi, Anniek Corveleyn, Dieter Nuyens
Journal: Circulation (2015)

Introduction: Sudden cardiac death in Brugada syndrome (BrS) is most frequent in rest or during sleep suggesting an influence of the autonomic nervous system. Some limited data indicate reduced QT rate dependence and loss of its diurnal variation in BrS. Hypothesis: We evaluated the hypothesis that QT rate dependence and its diurnal variation is reduced in BrS and assessed whether presence of an SCN5A mutation influences this relationship. Methods: In this retrospective single center study we included 4 different groups: patients demonstrating a spontaneous or ajmaline-induced type 1 ECG with (N=17) and without (N=19) SCN5A mutation, carriers of an SCN5A mutation without phenotypic evidence of BrS based on serial ECG’s and provocation with ajmaline (N=22) and finally genotype negative family members of SCN5A mutation carriers as controls (N=25). All patients underwent 24 hour holter recordings. QT/RR analysis of 24 hour, daytime (8AM-9PM) and nighttime (11PM-6AM) data was performed along with manual review. Results: Age and sex were comparable between groups, as was the use of a beta-blocker (9 in the total group). 24 hour QT/RR slope was reduced both in the SCN5A positive (0.141±0.045; p=0.04) and negative BrS group (0.141±0.047; p=0.03) as in the phenotype negative genotype positive group (0.128±0.046; p=0.001) compared to controls (0.183±0.054). Daytime QT rate dependence remained significantly reduced in the 3 pathological states, however nighttime QT rate dependence was not. In controls there was a trend towards a diurnal variation of QT rate dependence (QT/RR slope day 0.152±0.063; night 0.129±0.05; p=0.13), however this was not the case in any of the other groups. There was a clear trend towards lower values in 10 symptomatic BrS patients (0.118±0.045) compared to 26 asymptomatic BrS patients (0.15±0.043; p=0.06). Conclusions: In this large cohort of BrS patients, QT rate dependence was reduced during 24 hour and daytime periods without evidence of diurnal variation and independent of the presence of an SCN5A mutation. This attenuation of QT rate dependency further underscores the role of a pathological response to autonomic nervous system modulation in BrS arrhythmogenesis, irrespective of SCN5A genotypic status.
P2Y <sub>12</sub> -ADP Receptor Blockade in Chronic Kidney Disease Patients With Acute Coronary Syndromes
Authors: Laurent Bonello, Dominick J. Angiolillo, Daniel Aradi, Dirk Sibbing
Journal: Circulation (2018)

Because of its high prevalence, chronic kidney disease (CKD) remains a major health hazard throughout the world. Patients with CKD have a high prevalence and incidence of acute coronary syndromes (ACS). Despite decades of improved care, their higher risk profile persists and cardiovascular diseases remain their leading cause of death. Along with the reduction of glomerular filtration rate, several physiological processes are impacted and participate in the pathophysiology of ischemic and bleeding events. CKD is associated with an accelerated and severe course of atherothrombotic disease, and this relates to a modified vascular milieu with alterations on the level of the coagulation cascade and platelet aggregation. In addition, pharmacokinetics of several drugs, in particular antithrombotics, are altered and differ from that of non-CKD patients. Patients with CKD therefore represent a challenging population for both physicians and researchers. In addition to these perturbations of physiological processes, CKD patients face 2 major issues. First, there is a clear gap in scientific research as they are commonly underrepresented or excluded from major clinical trials. This is particularly true regarding antithrombotic treatment during ACS. Second, there is a gap in offering evidence-based treatment for these patients including state-of-the art options for revascularization and modern antiplatelet treatment, both of which are commonly underused. During the last decade, new potent oral P2Y 12 -ADP receptor antagonists, prasugrel and ticagrelor, which are more potent antiplatelet agents compared with clopidogrel, were introduced for ACS treatment. However, despite the fact that CKD patients represent a large proportion of those experiencing an ACS and are considered at high risk, there is a lack of dedicated trials and we are left with subgroup analysis of large randomized clinical trials were stage 4 and dialysis patients were rare. In the present review we summarize the mechanisms involved in the high ischemic and bleeding risk of CKD patients and the risk–benefit ratio of potent antiplatelet drugs during ACS.
RTHP-32. RECONSIDERING THE PROGNOSTIC IMPACT OF AGE, GRADE, AND EXTENT OF RESECTION ON CLINICAL OUTCOMES OF 1p/19q CODELETED OLIGODENDROGLIOMAS AFTER RADIATION THERAPY: A MULTI-INSTITUTIONAL REPORT
Authors: Alexander Lin, Liam Kane, Jason Molitoris, Deborah Smith, Shahed Badiyan, Tony Wang, Tim Kruser, Jiayi Huang
Journal: Neuro-Oncology (2018)

Age, grade, and extent of resection (EOR) are key factors to guide the treatment of gliomas. This multi-institutional study examines their prognostic impact on the favorable subset of molecularly-defined oligodendroglioma after definitive radiation therapy (RT). Grade 2–3 oligodendroglioma patients treated with RT with or without chemotherapy from 2000–2017 at four tertiary academic cancer centers were retrospectively reviewed. Eligible patients were required to have 1p/19q codeletion as well as defined grade and EOR within 12 months of RT. Progression-free survival (PFS) and overall survival (OS) rates were determined using Kaplan-Meier analyses. Cox regression analysis was used to identify factors associated with worse PFS and OS. One hundred sixty-eight patients were identified with median follow-up of 43 months (0.5–200). Median age was 46 (23–80), 79(47%) had gross-total resection, 121(72%) were grade 3; 106(63%) received adjuvant RT and temozolomide (TMZ), 26(15%) received adjuvant RT and procarbazine/lomustine/vincristine (PCV), 18(11%) received adjuvant RT alone, and 18(11%) received prior chemotherapy before salvage surgery and RT. Overall, the 10-year PFS and OS were 52% and 65%, respectively. On multivariable analysis, lower KPS (HR:0.96, 95% CI:0.93–0.99), gliomatosis (HR:195, 95% CI:16–2340), and prior chemotherapy (HR:2.2, 95% CI:1.04–4.7) were the only significant factors associated with worse PFS; notably, age, grade, and EOR were not significant for PFS. In a subset of 146 patients excluding those with gliomatosis and prior chemotherapy, age >40, grade 3, subtotal resection, TMZ chemotherapy, and lower RT dose were not associated with worse PFS or OS rates (all p >0.05). CONCLUSIONS: Oligodendrogliomas with 1p/19q codeletion have favorable outcomes after RT, except those with gliomatosis or prior chemotherapy exposure. Traditional prognostic factors of age >40, EOR, and grade do not appear to reliably risk stratify these patients after adjuvant RT. Their use to guide treatment selection may need to be revisited.
Abstract 15966: Is Insufficient Myocardial Blood Flow a Cause of Heart Failure?
Authors: Vahagn Ohanyan, Lindsey Rinker, Tatevik Hakobyan, Peter Hopmann, Molly Enrick, Christopher L Kolz, Liya Yin Yin, William M Chilian
Journal: Circulation (2017)

Heart failure (HF) afflicts about 5 million people in the US. Although current therapies have produced some measure of success in patient outcomes, they only slow the progression of the disease. We...
EXTH-35. IN VIVO 1H MRS DETECTS REDUCED 2HG PRODUCTION IN IDH1 MUTANT GLIOMAS TREATED WITH A DUAL PI3K/MTOR INHIBITOR
Authors: Georgios Batsios, Pavithra Viswanath, Anne Marie Gillespie, Elavarasan Subramani, Joanna J Phillips, Russell Pieper, Sabrina Ronen
Journal: Neuro-Oncology (2018)

70–90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase (IDH1mut). Mutant IDH produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis. Inhibitors of phosphoinositide-3-kinase (PI3K) pathway are currently under clinical investigation for IDH1mut gliomas with positive outcome results, but early response imaging biomarkers are missing. The goal of this study was to identify potential magnetic resonance (MR) detectable biomarkers of IDH1mut glioma response to the dual PI3K/mammalian target of rapamycin (mTOR) inhibitor XL765. We used two genetically-engineered IDH1mut models: a U87 glioblastoma-based model (U87IDHmut) and an immortalized normal human astrocyte-based model (NHAIDHmut), as well as a patient derived IDH1mut model (BT142). The reduction of PI3K/mTOR pathway signaling was validated with western blots of p4E-BP1 for all models. We then used MR spectroscopy (MRS) to investigate the impact of treatment on cell metabolism. Using 1H-MRS, we observed that XL765 induced a significant ~70% and ~50% reduction in steady-state levels of 2HG and glutamate in U87IDHmut while in NHAIDHmut the drop was ~90% and ~70% for 2HG and glutamate respectively. In the case of BT142 there was a ~35% drop in glutamate levels while 2HG was MRS undetectable in both groups. The translatability of our findings was evaluated in mice bearing orthotropic U87IDHmut xerographs treated with XL765 orally twice a day. XL765-treatment of mice led to an apparent slower tumor growth, which was associated with significantly increased animal survival. Importantly, in vivo 1H-MRS spectroscopy showed a significant reduction in 2HG levels. The results were verified by 1H-MRS of tumor extracts. Collectively, our results indicate that treatment with XL765 is associated with response in IDH1mut models. To our knowledge, this is the first time in vivo 1H-MRS detected reduction in 2HG in gliomas undergoing treatment with a non-IDH1mut-specific inhibitor. Thus, 2HG could potentially be used as a response biomarker.
Final Analysis of the Dose Escalation, Expansion and Biomarker Correlations in the Ph I/II Trial BGBC003 with the Selective Oral AXL Inhibitor Bemcentinib (BGB324) in Relapsed/Refractory AML and MDS
Authors: Sonja Loges, Michael Heuser, Joerg Chromik, Carlos E Vigil, Peter Paschka, Isabel Ben-Batalla, Nuray Akyüz, David Micklem, Robert Holt, Anthony Brown, James Lorens, Murray Yule, Maxim Kebenko, Melanie Janning, Mascha Binder, Walter Fiedler, Jorge E. Cortes, Bjorn Gjertsen
Journal: Blood (2018)
PDTM-02. STRESS GRANULES ARE INDUCED BY OXIDATIVE STRESS IN PEDIATRIC BRAIN TUMORS AND PREDICT POOR OUTCOME
Authors: Alberto Delaidelli, Gian Luca Negri, Brian Cho, Sean Minaker, Amal El Naggar, Juliette Hukin, Stephen Yip, Mariarita Santi, John Maris, Poul Sorensen
Journal: Neuro-Oncology (2018)

BACKGROUND/OBJECTIVES: Brain tumors represent the most common and aggressive pediatric cancer type, underscoring a dire need for novel therapeutic approaches. Tumors are continually exposed to acute changes in their microenvironment, including oxidative stress. To overcome acute stress, cells form stress granules (SGs), clusters of RNA and RNA-binding proteins (RBPs) that rapidly alter the cellular mRNA translation landscape. Preliminary data indicate that pharmacological inhibition of SG formation blocks the antioxidant response of the transcription factor NRF2 (NFE2L2), impairing pediatric sarcoma invasive and metastatic capacity. We therefore set out to determine if pediatric brain tumors rely on SGs to overcome oxidative stress, and if targeting SGs could represent a therapeutic approach for these tumors. We analyzed public databases for links between mRNA expression of the RBP G3BP1 and NFE2L2. Immunohistochemistry (IHC) for G3BP1, NRF2 and oxidative stress markers (4HNE) was performed on atypical theratoid rabdoid tumor (AT/RT), pediatric glioblastoma (pGBM) and ependymoma (EPN) tissue microarrays. AT/RT, pGBM and EPN cell lines were treated with NaAsO2 and H2O2 to induce oxidative stress and SG presence was determined by ImmunoFluorescence for the RBPs G3BP1 and TIA-1. G3BP1 and NFE2L2 expression positively correlates in several pediatric tumor cohorts, including AT/RT, pGBM and EPN (p<0.01). IHC not only confirmed mRNA results, but revealed that G3BP1 over-expression is linked to higher WHO grade and recurrent disease in EPN. High G3BP1 levels are also predictive of poor outcome in pGBM (p<0.05). Finally, oxidative stress induces the RBPs G3BP1 and TIA-1 to form SGs in vitro. CONCLUSIONS: SGs represent an important mediator for the adaptive response of pediatric brain tumors to acute oxidative stress. Inhibiting SG formation might therefore constitute a therapeutic approach for AT/RT, pGBM and EPN. Future studies will aim at confirming the efficacy of drugs that inhibit SG formation in pediatric brain tumors.
Abstract 14677: Reversal of Angiotensin-(1-12)-Caused Positive Modulation on Left Ventricular Contractile Performance in Heart Failure: Assessment by Left-Ventricular Pressure-Volume Analysis
Authors: Tiankai Li, Zhi Zhang, Xiaowei Zhang, Sarfaraz Ahmad, Zhe Chen, Jasmina Varagic, Santiago R Ramirez, Heng-Jie Cheng, Carlos Ferrario, Che Ping Cheng
Journal: Circulation (2017)

Background: Angiotensin-(1-12) [Ang-(1-12)] is a renin-independent precursor for direct angiotensin II (Ang II) production by chymase. Substantial evidence suggests that heart failure (HF) may alte...
ATIM-25. NEOADJUVANT PD-1 ANTIBODY BLOCKADE IS ASSOCIATED WITH FOCAL UPREGULATION OF PD-L1 AND CD8 T CELL INFILTRATE IN RECURRENT GLIOBLASTOMA
Authors: Joey Orpilla, Aaron Mochizuki, Jeremy Reynoso, Neha Akkad, Alexander Lee, Tom Davidson, Linda Liau, Timothy Cloughesy, Robert Prins
Journal: Neuro-Oncology (2018)

The use of anti-PD-1 therapy, pembrolizumab, has shown minimal therapeutic effect as an adjuvant treatment in glioblastoma, but its efficacy as a neoadjuvant in recurrent glioblastoma setting has yet to be established. The Ivy Foundation Early Phase Clinical Trials’ Consortium conducted a randomized, multi-institution Phase I clinical trial to evaluate the immune response and survival following neoadjuvant and adjuvant therapy with pembrolizumab in thirty patients with recurrent, surgically resectable glioblastoma. Formalin-fixed paraffin embedded tissue was stained using multiplex immunohistochemistry to spatially visualize and quantify the following markers: CD8, PD-1, CD45, GFAP, and PD-L1. The density of tumor infiltrating CD8 T-cells was not statistically different between groups, but distinctly variable in the neoadjuvant treatment group. PD-1 expression across both treatment groups co-localized with CD8 T-cells, though 9 neoadjuvant and only 3 adjuvant samples had appreciable PD-1 detected. Samples with the highest percentage of PD-L1 expression and double positive CD8/PD-1 cell population were present in both groups. Notable CD45/PD-L1 populations were found in 3 neoadjuvant treated samples, with only 1 in the adjuvant group. Samples were classified as having either constitutive, focal, or negative PD-L1 expression pattern with varying degrees of CD8 infiltrate. 7 neoadjuvant patients and 3 adjuvant patients exhibited a focal phenotype with a high CD8 infiltrate. Neoadjuvant samples exhibiting focal PD-L1 expression also had a higher median survival compared to the corresponding adjuvant group (p=0.035, Mantel-Cox log rank). CONCLUSION: Classification of tumors based on PD-L1, CD8, and PD-1 IHC may be predictive of outcome and therapeutic effect. We identified a subset of patients with focal expression of PD-L1 with increased survival. This suggests that focally expressed PD-L1, perhaps induced on tumor and immune infiltrate by the presence of an anti-tumor CD8 response, is a biomarker that is predictive of a positive response to anti-PD-1 checkpoint blockade.
Low-Dose Methotrexate for the Prevention of Atherosclerotic Events
Authors: Paul M Ridker, Brendan M. Everett, Aruna Pradhan, Jean G. MacFadyen, Daniel H. Solomon, Elaine Zaharris, Virak Mam, Ahmed Hasan, Yves Rosenberg, Erin Iturriaga, Milan Gupta, Michelle Tsigoulis, Subodh Verma, Michael Clearfield, Peter Libby, Samuel Z. Goldhaber, Roger Seagle, Cyril Ofori, Mohammad Saklayen, Samuel Butman, Narendra Singh, Michel Le May, Olivier Bertrand, James Johnston, Nina P. Paynter, Robert J. Glynn
Journal: New England Journal of Medicine (2018)

Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit.We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point.The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo.Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).
Retracted: Decoy Oligodeoxynucleotides, Polysaccharides, and Targeted Peptide‐Functionalized Gold Nanorods for the Combined Treatment of Rheumatoid Arthritis
Authors: Nan Zhang, Shasha Zhang, Chunyu Xu, Lingling Fu, Tuanbing Liu, Yongxing Zhao
Journal: Advanced Healthcare Materials (2018)

Abstract Autoimmune diseases like rheumatoid arthritis (RA) possess complicated pathogenesis. Therefore, RA is hard to treat by monotherapies in clinical setting. All‐in‐one treatments that target inflamed joints and act efficiently are highly needed. Gold compounds are old anti‐RA therapies and are fabricated into gold nanorods (GNRs) that serve as anti‐RA therapeutics as well as nanocarriers for anti‐inflammatory nucleic acid drug‐NF‐κB‐decoy oligodeoxynucleotides (dODNs). A targeted peptide to vascular cell adhesion molecule‐1 (VCAM‐1) (P VCAM‐1 ) is modified onto the GNRs to facilitate enhanced accumulation of GNRs in inflamed tissues and enhanced cellular uptake of GNRs by inflamed cells. dODNs loaded and P VCAM‐1 modified GNRs (GNRs‐dODN‐P VCAM‐1 ) are covered by polysialic acid (PSA) to protect GNRs‐dODN‐P VCAM‐1 in vivo. Simultaneous GNRs, dODN, and thermotherapy show synergic effect on the reduction of TNF‐α and IL‐6 in inflamed macrophages and blood vessel cells. The simultaneous triple therapy (GNRs‐dODN‐PSA‐P VCAM‐1 +laser) demonstrates excellent anti‐inflammatory efficacy in vitro and in vivo.
CSIG-17. CHARACTERIZATION OF AN ALTERNATIVELY SPLICED NTRK2 VARIANT IN GLIOMA: EMPLOYING NOVEL REAGENTS TO UNCOVER NOVEL FUNCTIONS
Authors: Siobhan Pattwell, Sonali Arora, Patrick Cimino, Tatsuya Ozawa, Benjamin Hoffstrom, Norman Boiani, Hamid Bolouri, Keith Loeb, Colin Correnti, John Silber, Eric Holland
Journal: Neuro-Oncology (2018)

Most known for their essential roles in the development and maintenance of the nervous system, the neurotrophins consist of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), NT-3, NT-4 and their respective tropomyosin receptor kinases (TRKs) TrkA, TrkB, and TrkC along with the low affinity nerve growth factor receptor, p75. In addition to known roles in neuronal survival, proliferation, differentiation, and apoptosis, TRKs exert diverse effects on cellular outcomes through their interactions with downstream signaling cascades. Prior to TRKs’ established roles in neurobiology, oncogenic TRK was discovered as tropomysoin 3 (TPM3)-TrkA fusion and as a result, oncological studies of the neurotrophin family have identified additional TRK fusions. Putative oncogenic TRK fusions have been observed in various cancer types, but their clinical significance remains unclear and these fusions tend to occur at very low frequencies below 1–2%. The low incidence of these fusions combined with significant overexpression of various TRKs in a multitude of cancers raises the possibility that another aspect of TRK biology, in addition to kinase-domain fusions, may be relevant. Basic scientific and clinical investigation surrounding TRKs’ role in cancer has often been hindered due to the nonspecific nature of antibodies and kinase inhibitors, combined with a lack of precise exon-specific expression data from patient populations. Tropomyosin receptor B (TrkB), encoded by the NTRK2 gene, exhibits complex alternative splicing patterns. Here we show a novel role for a TrkB splice variant in gliomas via NTRK2 transcript analyses and immunostaining using a novel antibody engineered specifically to this variant. This NTRK2 splice variant enhances PDGF-driven gliomas in vivo and augments PDGF-induced signaling in vitro. Through the lens of NTRK2, these results highlight the importance of expanding upon whole gene-level and kinase-fusion analyses to explore TRK splicing in basic and translational research.