tbuckley/cabot-search huggingface dataset:
MEDU-24. INTERROGATING THE ROLE OF EPIGENETIC REGULATORS IN MYC-DRIVEN MEDULLOBLASTOMA
Authors: Jennifer Stripay, Marie Morfouace, Christopher Vakoc, Martine Roussel
Journal: Neuro-Oncology (2019)

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is characterized by four molecularly and histopathologically distinct groups with different prognoses. With the advent of next generation sequencing, the field has gained new insights into somatically altered genes in MB, many of which are involved in epigenetic gene regulation and chromatin modification. A significant portion of Group 3 MB do not carry any mutations, suggesting that additional, non-mutated, epigenetic regulators may be implicated in shaping chromatin structure and driving tumor pathogenesis. Considering this possibility, we conducted two unbiased screens of epigenetic regulators in G3 MB to identify candidate drivers of medulloblastoma genesis. 1) In collaboration with Dr. Christopher Vakoc, we screened a library of shRNAs targeting 293 known chromatin modifiers in mouse G3 MB cells. Designed to assess reduction in viability, the dropout screen identified putative oncogenes, and of the top hits, SMYD3, a lysine methyltransferase, emerged as the most interesting candidate. SMYD3 is overexpressed and exhibits increased predicted activity in G3 MB compared to other subgroups. Perturbation of SMYD3 using shRNA or CRISPR/Cas9 results in significantly reduced tumor progression and significantly prolonged lifespan in tumor-bearing animals. 2) We also screened a pooled epigenetic CRISPR/Cas9 gRNA library in G3 MB cells where we assessed gRNA enrichment in vivo and thus, identified putative tumor suppressors. Based on biological relevance and computational prediction, PRDM2 was selected as the top candidate. Implicated in other cancers, PRDM2, a histone 3 lysine 9 methyltransferase, exhibits low expression and predicted activity in G3 MB compared to other subgroups. Current work is focused on dissecting the epigenetic, transcriptomic, and phenotypic consequences of PRDM2 perturbation in naïve neural progenitors and G3 MB cells. Taken together, these efforts will help us to understand how changes in chromatin modifiers affect disease pathogenesis and how these changes may represent therapeutic vulnerabilities.
Outcomes of Percutaneous Coronary Intervention and Coronary Artery Bypass Graft Surgery for Multivessel Coronary Artery Disease
Authors: Sripal Bangalore, Ziad A. Ali, Gregg W. Stone
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
HGG-21. AN OMICS APPROACH TO ELUCIDATING THE MECHANISM OF ETV5 IN PEDIATRIC GLIOMA
Authors: Hannah Park
Journal: Neuro-Oncology (2019)

Gliomas are the most common CNS tumors in pediatric patients. Tumorigenesis for these young patients occur at a key neurodevelopmental window and it is believed that developmental and differentiation pathways are exploited during the transformation of CNS cells. We have shown that Etv5 is necessary for tumor initiation and regulates the unhinged gliogenesis observed in our novel mouse model of pediatric high-grade glioma (HGG). While the role of oncogenic ETV5 in various cancers is well-established, its role in HGGs has yet to be determined. We are currently pursuing an omics approach to identifying the post-translational mechanisms regulating ETV5 function and stability in HGG. Additionally, we have developed a single-copy expression system to perform genomic analysis and identify downstream targets of ETV5 in transformed human pediatric glioma. We provide evidence that ETV5 may be involved in inducing a glial cell-fate in tumor cells which is believed to be a necessary cell type in these devastating tumors.
US medical school abandons affirmative action after pressure from Trump administration
Authors: Owen Dyer
Journal: BMJ (2019)

The medical school of Texas Tech University, under pressure from the US education department, has agreed to stop considering race as a criterion in its admissions, becoming the first institution to bend before the Trump administration’s campaign to end affirmative action in US universities.

The move is evidence that the administration’s hostility to affirmative action policies that seek to bring more black and Hispanic students into higher education is having an effect, say civil rights groups.

It follows last year’s revoking by the education secretary, Betsy DeVos, of the Obama administration guidance that advised schools on how they could legally consider race in the interest of promoting diversity. DeVos has previously fought against affirmative action.

Her department’s Office for Civil Rights is already investigating the use of race in admissions at Harvard and Yale universities, questioning whether Asian American applicants are being discriminated against.

Vanita Gupta, president of the Leadership Conference Education Fund, a civil rights umbrella group opposing discrimination in education, said, “Not only is this administration demonstrably hostile toward diversity and inclusion in our higher education institutions, but now it is also pressuring …
High mitochondrial DNA copy number is associated with longer survival in young patients with glioblastoma
Authors: Laure-Marie Dardaud, Céline Bris, Valérie Desquiret-Dumas, Blandine Boisselier, Emeline Tabouret, Karima Mokhtari, Dominique Figarella-Branger, Audrey Rousseau, Vincent Procaccio
Journal: Neuro-Oncology (2019)

Glioblastoma (GB) is the most common and most aggressive form of diffuse glioma, with a median overall survival of 15 months after standard of care.1 Young GB patients (
HGG-17. NEW PHARMACOLOGICAL APPROACHES IN GLIOBLASTOMA THERAPY: BIOLOGICAL EFFECTS AND MOLECULAR ALTERATIONS
Authors: Anna Lisa Iorio, Martina Da Ros, Veronica De Gregorio, Laura Giunti, Lorenzo Genitori, Iacopo Sardi
Journal: Neuro-Oncology (2019)

INTRODUCTION: Although decades of research have been trialed, the prognosis for patients with glioblastoma (GBM) has not significantly changed, highlighting the urgency of innovative strategies. Therefore, we investigated on GBM preclinical models the potential of a new pharmacological approach, combining doxorubicin (Dox), a historical anticancer agent with a high toxicity in vitro, and rapamycin (Rapa), a potent inhibitor of cell proliferation. METHODOLOGIES: We analyzed the synergistic effect obtained using Dox combined to Rapa on A172, U87MG and T98G GBM cell lines. MTT and TUNEL analysis were used to assess cytotoxicity and apoptosis. We also evaluated the effectiveness of the treatment in an orthotopic xenograft mice model of GBM with U87MG-luc cells by treatment with Dox, Rapa and their combination. At the end of experiments, brain tissues were collected for histological analysis. RESULTS: In vitro results showed that T98G was resistant to Dox but sensible to Rapa. Prolonging treatments, we observed a significant difference comparing Rapa vs Dox plus Rapa groups (p<0,001), indicating that Rapa sensitizes T98G to Dox. In vivo results showed that Rapa and Dox determined a tumor growth inhibition from 86% to 97%; the most important action was given by Rapa plus high Dox treatment (-97%). However, this combination resulted in greater toxicity. It would be more appropriate to use Rapa plus lower Dox, which shows a tumor inhibition similar to Rapa plus high Dox with a lower toxicity. CONCLUSIONS: More studies are necessary to well understand the appropriate schedule of co-treatment but, this safe and non-invasive approach could be a successful strategy to increase the quality of life and survival rate of “poor-responder” brain tumor patients.
Paclitaxel and Alisertib in Recurrent Ovarian Cancer—In Reply
Authors: Gerald Falchook, Robert L. Coleman, Russell J. Schilder
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Validation of the ELN 2017 Classification for AML with Intermediate Risk Cytogenetics with or without NPM1 -Mutations and High or Low Ratio FLT3-ITD s
Authors: Johannes Schetelig, Christoph Rollig, Sabine Kayser, Friedrich Stoelzel, Kerstin Schaefer-Eckart, Mathias Haenel, Wolf Roesler, Hermann Einsele, Martin Kaufmann, Hubert Serve, Gesine Bug, Alwin Kraemer, Wolfgang E. Berdel, Matthias Stelljes, Jiri Mayer, Albrecht Reichle, Claudia D. Baldus, Norbert Schmitz, Jan Moritz Middeke, Michael Kramer, Gerhard Ehninger, Martin Bornhäuser, Christian Thiede
Journal: Blood (2017)
Insulin Resistance and Cancer-Specific and All-Cause Mortality in Postmenopausal Women: The Women’s Health Initiative
Authors: Kathy Pan, Rebecca A Nelson, Jean Wactawski-Wende, Delphine J Lee, JoAnn E Manson, Aaron K Aragaki, Joanne E Mortimer, Lawrence S Phillips, Thomas Rohan, Gloria Y F Ho, Nazmus Saquib, Aladdin H Shadyab, Rami Nassir, Jinnie J Rhee, Arti Hurria, Rowan T Chlebowski
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background Insulin resistance has been proposed as a mediator of the increased cancer incidence and mortality associated with obesity. However, prior studies included limited cancer deaths and had inconsistent findings. Therefore, we evaluated insulin resistance and cancer-specific and all-cause mortality in postmenopausal women participating in the Women’s Health Initiative (WHI). Methods Eligible were a subsample of 22 837 WHI participants aged 50–79 years enrolled at 40 US clinical centers from 1993 to 1998 who had baseline fasting glucose and insulin levels. Baseline insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Cancers were verified by central medical record review and deaths verified by medical record and death certificate review enhanced by National Death Index queries. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality. All statistical tests were two-sided. Results During a median of 18.9 years of follow-up, 1820 cancer deaths and 7415 total deaths occurred. Higher HOMA-IR quartile was associated with higher cancer-specific mortality (Q4 vs Q1, HR = 1.26, 95% CI = 1.09 to 1.47; Ptrend = .003) and all-cause mortality (Q4 vs Q1, HR = 1.63, 95% CI = 1.51 to 1.76; Ptrend &amp;lt; .001). A sensitivity analysis for diabetes status did not change findings. Among women with body mass index less than 25 kg/m2, higher HOMA-IR quartile was associated with higher cancer mortality (Fine and Gray, P = .004). Conclusions High insulin resistance, as measured by HOMA-IR, identifies postmenopausal women at higher risk for cancer-specific and all-cause mortality who could potentially benefit from early intervention.
The VA MISSION Act — Creating a Center for Innovation within the VA
Authors: Ashok Reddy, Stephan D. Fihn, Joshua M. Liao
Journal: New England Journal of Medicine (2019)

The VA MISSION Act dedicates $50 million per year to a new Department of Veterans Affairs innovation center and would allow it to prioritize pilots that counterbalance underlying incentives, test episode-based payment approaches, and address veteran-specific needs.
Abstract 12135: Toll-like Receptor Signalling Mediates C-kit+ Cell Migration <i>in vivo</i> Following Ischemia-reperfusion Injury via the Myd88 Pathway
Authors: Peter Donndorf, Saifullah Abubaker, Alexander Kaminski, Brigitte Vollmar, Gustav Steinhoff
Journal: Circulation (2015)

Introduction: Toll-like-receptor (TLR) mediated signalling has been shown to regulate tissue damage following cardiac ischemia-reperfusion (I-R) injury. Whether progenitor cell based cardiac regeneration might also depend on TLR-signaling has not been described conclusively. As sufficient progenitor cell migration represents a crucial step of cell-based therapy protocols, we aimed at analyzing the migratory capacity of c-kit+ bone marrow stem cells in vivo following I-R injury as well as the impact of endothelial TLR's and related signalling pathways (MyD88,TRIF)on c-kit+ cell migration. Methods: Murine c-kit+ stem cells were isolated from the bone marrow. In vivo migration of fluorescently labeled c-kit+ following different extents of local I-R injury was visualized by intravital fluorescence microscopy, utilizing the cremaster muscle model in male mice.C-kit+ cell migration was quantified by analyzing early (endothelial rolling) and late (firm endothelial adhesion) c-kit+ cell interaction with the local endothelium. The role of TLR-2 and TLR-4, as well as MyD88 and TRIF on c-kit+ migration following I-R-injury was analyzed by applying specific knock-out models. Results: A sequence of 15 min ischemia followed by 15 min reperfusion induced relevant interactions of c-kit+ cells with the microvascular endothelium(Firm endothelial adhesion:5.6±1.3 cells/mm2 in control vs. 30.2±10.1 cells/mm2 in IR, p&lt;0.05). Prolonged I-R periods did not result in an additional gain of c-kit+ cell-endothelial cell interaction. Knock-out of TLR-2 and TLR-4 diminished I-R induced c-kit+ - endothelial cell interaction.Subsequent knock-out of downstream adaptor proteins resulted in a significantly decreased firm endothelial c-kit+ cell adhesion only for MyD88 but not for TRIF. Conclusions: Artificially applied c-kit+ cells are capable to interact with the target organ endothelium following I-R injury. C-kit+ cell-endothelial cell interaction following I-R injury depends on TLR associated signaling, with a special relevance being demonstrated here for the MyD88 pathway. Our findings suggest, that therapeutic blockade of TLR signaling following I-R injury for anti-inflammatory purposes might interfere with progenitor cell based therapy protocols.
DETECTION OF BARRETT'S ESOPHAGUS THROUGH EXHALED BREATH USING A NON-INVASIVE SCREENING TOOL
Authors: Y Peters, RWM Schrauwen, AC Tan, SK Bogers, B de Jong, PD Siersema
Journal: Endoscopy (2019)

Timely detection of esophageal adenocarcinoma and its precursor Barrett's esophagus (BE) may decrease both cancer mortality and incidence. Currently, an accurate, minimally-invasive screening method for BE for widespread use not available. Our objective was to establish the accuracy with which breath analysis could discriminate patients with BE from controls without BE.
Notice of Retraction and Replacement. Choi et al. Risk of hepatocellular carcinoma in patients treated with entecavir vs tenofovir for chronic hepatitis B: a Korean nationwide cohort study. <i>JAMA Oncol.</i> 2019;5(1):30-36
Authors: Young-Suk Lim, Min Jung Ko
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
IMMU-05. COMBINATIONAL CAR T-CELL AND EPIGENETIC MODIFIER THERAPY TO TARGET POSTERIOR FOSSA TUMORS
Authors: Laura Donovan, Kevin Bielamowicz, Sujith Joseph, Alberto Delaidelli, Poul Sorenson, Nabil Ahmed, Michael Taylor
Journal: Neuro-Oncology (2019)

Posterior Fossa tumours (PFTs) are the leading cause of cancer-related death in children, with medulloblastoma and ependymoma (EP) the most prevalent. PFTs continue to be treated with non-specific toxic therapies, with survivors suffering life threatening morbidities. PFTs are known to have distinct molecular sub-types; here we focus on two PFTs—Group 3 medulloblastoma and Posterior Fossa A (PFA) EP—which have the worst outcomes and are restricted to children. Actionable and recurrent mutations are rare in these PFTs; we recently confirmed the presence of three Chimeric Antigen Receptor (CAR) target antigens, EPHA2, HER2 and IL13R2, for use as mono-CARs, TRI CARs, and in combinational therapy with the epigenetic modifier Azacitidine. Pre-clinical trials showed CAR delivery via the lateral ventricle gave the most significant survival benefit (P<0.0005), therefore all downstream therapies were delivered intrathecally. Group 3 medulloblastoma: trials using one treatment round (1R) of EPHA2 CARs showed significant tumor regression versus T cell (P<0.005) and no-treatment (NT) (P<0.0005). The use of 2Rs of EPHA2 CARs to target tumor recurrence resulted in significant tumor regression (P<0.0005) versus NT, with progression-free survival (PFS) observed at >500 days post therapy. Combination therapy of 1R EPHA2 CARs with Azacitidine gave significant tumor regression versus EPHA2 CARs alone (P<0.0005). PFA EP: trials using HER2 (P<0.05) or TRI CARs (P<0.005) showed significant tumor regression versus T cell controls, and most subjects showed increased PFS. CARs with combinational Azacitidine therapy resulted in PFS in every PFA EP subject. We show that intrathecal CAR therapy combined with Azacitidine significantly increases survival rates in Group 3 medulloblastoma and PFS for PFA EP. Results from this project have created a paradigm shift in the treatment of PFTs, with the initiation of a clinical trial for HER2+ PFA EP treatment, and the capacity for future clinical trials for Group 3 medulloblastoma.
ATRT-02. THERAPEUTIC TARGETING OF EZH2 AND BET BRD4 IN AT/RT
Authors: Ali Zhang, Andrea Piunti, Patrick Ozark, Xingyao He, Hiroaki Katagi, Takahiro Sasaki, Kathryn Laurie, Stewart Goldman, Lihua Zou, Ali Shilatifard, Rintaro Hashizume
Journal: Neuro-Oncology (2019)

Atypical teratoid/rhabdoid tumors (AT/RTs) are lethal childhood cancers and defined by inactivation of the SMARCB1 tumor suppressor gene encoding a chromatin remodeling complex which suppresses activity of EZH2 methyltransferase. The absence of SMARCB1 protein promotes increased EZH2 activity, results in increased methylation of histone H3 lysine 27 (H3K27), which is generally associated with transcriptional repression. H3K27 can also be acetylated, which requires bromo- and extra-terminal domain (BET) protein activity to activate transcription. Recent genome-wide ChIP-sequence analyses identified high occupancy of H3K27ac in association with BET bromodomain-containing protein 4 (BRD4) at super-enhancer elements in AT/RT. The aberrant activity of EZH2 and BRD4 histone modifiers is of fundamental importance to the occurrence and biology of AT/RT and actionable targets for treating AT/RT. We tested the effects of targeting inhibition of EZH2 and BRD4 in AT/RT. BRD4 inhibitor JQ1 induced dose-dependent growth inhibition of AT/RT cells with decreased expression of H3K27ac, and combination treatment of EZH2 inhibitor (GSK126) and JQ1 resulted in further suppressed the cell growth and cell invasion relative to either monotherapy. RNA sequence analysis showed differentially expressed genes in response to each treatment and slightly overlap genes associated with JQ1 and GSK126 treatment. We treated the mice with GSK-126 and JQ1 for 3 weeks. Combination therapy suppressed the tumor growth and prolonged animal survival in compared to monotherapy in the mice with intracranial AT/RT xenografts. Collectively, these findings suggest that therapeutic combination of EZH2 and BRD4 inhibitor provides a rational epigenetic targeted therapy for AT/RT.
Abstract 14541: Improving Physical Activity and Decreasing Hopelessness in Patients With Ischemic Heart Disease: Testing of the Heart Up! Intervention
Authors: Susan L Dunn, Lorraine B Robbins, Sandi W Smith, Rajiv Ranganathan, Holli A DeVon, James A Schafer, Nathan L Tintle
Journal: Circulation (2017)

Introduction: Rates of physical activity (PA) in adults with ischemic heart disease (IHD) continue to be unacceptably low and enrollment in hospital-based cardiac rehabilitation (CR) is abysmal. Co...