tbuckley/cabot-search huggingface dataset:
DIPG-07. EPIGENOME SCREENING IDENTIFIES TRANSCRIPTIONAL ELONGATION AS THERAPEUTIC VULNERABILITY IN H3K27M-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Nathan Dahl, Ilango Balakrishnan, Dong Wang, Etienne Danis, Krishna Madhavan, Susan Fosmire, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2019)

Mutations in the histone 3 (H3) gene (H3K27M) are the eponymous driver in diffuse intrinsic pontine gliomas (DIPGs), aggressive pediatric brain tumors for which no curative therapy currently exists. In order to identify specific epigenetic dependencies which arise as a consequence of the H3K27M mutation, we performed an shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in patient-derived DIPG cell lines. This identified AFF4, a component of the super elongation complex (SEC), as both highly expressed and necessary for DIPG cells to maintain growth and self-renewal. We hypothesized that SEC overexpression occurs as a direct consequence of the H3K27M mutation and that this relative abundance overcomes repressive transcriptional regulation in order to suppresses differentiation and promote self-renewal of DIPG tumor stem cells. We found that AFF4 expression is consistently elevated in both DIPG patient samples and established cell lines relative to normal pediatric pons. We interrogated the role of AFF4 in H3K27M-mutant DIPG using an shRNA lentiviral approach. Using live cell imaging, we demonstrate a significant decrease in in vitro clonogenicity and stem cell maintenance following AFF4 depletion. We employed RNA-seq-based gene set enrichment analysis to delineate differentiation programs under AFF4 regulatory control. Finally, we sought to determine whether CDK9, the catalytic subunit of the SEC, represents a therapeutic vulnerability in DIPG. Using ChIP-seq following CDK9 pharmacologic inhibition, we demonstrate that the loss of regulatory transcriptional input in DIPG may be reversed via CDK9 inhibition and that this acts as a potent inhibitor of DIPG cell growth both in vitro and in vivo orthotopic xenograft models. These studies represent the first pre-clinical validation of SEC inhibition as a novel therapeutic approach in DIPG.
Low-cost stepped intervention to increase influenza vaccination rates at a Comprehensive Cancer Center.
Authors: Petros Grivas, Sumana Devata, Rami Khoriaty, Philip S. Boonstra, Joshua Michael Ruch, Kevin McDonnell, Leonel Fernando Hernandez-Aya, Joshua Murray Wilfong, Jeffrey B. Smerage, Michael G Ison, Joseph NS Eisenberg, Maria Silveira, Kathleen A. Cooney, Francis P. Worden
Journal: Journal of Clinical Oncology (2015)

e17654 Background: Influenza morbidity and mortality can be severe and costly, especially for cancer patients who are often immuno-compromised. However, vaccination rates remain suboptimal in cancer patients due to provider- and patient-related factors. We hypothesized that a low-cost provider- and patient-focused intervention would increase influenza vaccination rates at the University of Michigan Comprehensive Cancer Center (UMCCC). Methods: This quality improvement projectincluded allpatients without documentation of influenza vaccination prior to their first outpatient appointment during 2011-2012 and 2012-2013 influenza seasons. The multi-stepped intervention included provider and patient reminders. Influenza vaccination rates were compiled using CPT4 codes. Same day (with any UMCCC appointment) vaccination rates during the intervention seasons were compared to historical (2005-2011) controls; vaccination rates were also compared to a contemporary control population within University of Michigan Health System (UMHS) not seen at UMCCC and not exposed to intervention. Reasons for non-adherence with vaccination were described. Results: The cumulative same-day vaccination rate in eligible adults was 10.1% (2011-2012) and 9.4% (2012-2013) compared to an average 6.9% during influenza seasons 2005-2011. Based on logistic regression analysis, there was a 37.6% (95%CI 35-40.3%) and 56.1% (95%CI 40.9-73%) relative increase in the adult vaccination rate due to the intervention, associated with 399 and 697 additional vaccinations, respectively, for each season. During the 2012-2013 season the UMCCC adult vaccination rate was higher compared to the remainder of UMHS.The intervention was well accepted by providers. Reasons for no vaccination were both provider and patient related. Conclusions: Increasing provider and patient awareness with a simple, inexpensive, stepped intervention increased influenza vaccination rates at a large academic Cancer Center. The intervention is permanently implemented during influenza seasons.
Will the steerable capsule replace upper endoscopy in the future?
Authors: Martin Keuchel
Journal: Endoscopy (2019)

Disruptive wireless capsule endoscopy technology has evolved to become a first-line diagnostic tool for the small bowel and is also available for the colon. A major obstacle to conquering the last realm of the gastrointestinal (GI) tract is the spacious anatomy of the stomach, with its unpredictable motility.
MEDU-07. THE DEVELOPMENTAL STAGE OF THE MEDULLOBLASTOMA CELL-OF-ORIGIN IS MAINTAINED IN CANCER AND RESTRICTS HEDGEHOG PATHWAY USAGE AND DRUG SENSITIVITY
Authors: Marlinde Smit, Inna Armandari, Irena Bockaj, Tosca Martini, Walderik Zomerman, Zillah Siragna, Tiny Meeuwsen-de Boer, Frank Scherpen, Mirthe Schoots, Martha Ritsema, Wilfred den Dunnen, Eelco Hoving, Judith Paridaen, Gerald de Haan, Victor Guryev, Sophia Bruggeman
Journal: Neuro-Oncology (2019)

Sonic Hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) population that depends on Hedgehog signaling for its expansion. While SHH tumors are characterized by an overall deregulation of this pathway, they also exhibit aberrations that are specific for patient age. To investigate if the developmental stage of the tumor cell-of-origin can account for these age-specific lesions, we compared transcriptomes from developing mouse CGNPs and observed highly dynamic gene expression changes as function of age. Cross-species comparison with a cohort of SHH medulloblastoma showed partial maintenance of these patterns in the different medulloblastoma patient-age groups. In particular, we found low primary cilia expression in early CGNPs and infant medulloblastoma, which coincided with insensitivity to Smoothened manipulation. Together, these findings can explain the absence of SMOOTHENED mutations in infant patients and suggest that drugs targeting the SHH pathway downstream of SMOOTHENED will be most appropriate for infant patients.
Abstract 15188: Basal Epac2 Activation Regulates Spontaneous Beating of Cardiac Pacemaker Cells
Authors: Tatiana M Vinogradova, Kirill V Tarasov, Edward G Lakatta
Journal: Circulation (2017)

Spontaneous firing of sinoatrial node cells (SANC) is regulated by submembrane local Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR). Spontaneous LCRs appear during diastolic depolarization (...
Abstract 20371: Prognostic Impact of Peak Mitral Inflow Velocity in Asmptomatic Degenerative Mitral Regurgitation
Authors: Chisato Okamoto, Atsushi Okada, Hideaki Kanzaki, Yasuhiro Hamatani, Hiroyuki Takahama, Makoto Amaki, Takuya Hasegawa, Yasuo Sugano, Tomoyuki Fujita, Junjiro Kobayashi, Satoshi Yasuda, Toshihisa Anzai
Journal: Circulation (2017)

Introduction: Management of asymptomatic patients with severe mitral regurgitation (MR) and preserved EF is often challenging, and appropriate timing of mitral valve surgery remains controversial. ...
MEDU-03. CHARACTERIZATION OF THE ROLE OF L3MBTL3 IN MEDULLOBLASTOMA TUMORIGENESIS
Authors: Honglai Zhang, Ester Calvo Fernandez, Claire Peabody, Rork Kuick, Sung-Soo Park, Thomas Saunders, Sandra Camelo-Piragua, Jeff-Francois Rual
Journal: Neuro-Oncology (2019)

Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements but are achieved at a high cost to quality of life. The Notch pathway governs cell proliferation in many biological contexts, including medulloblastoma tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of Notch for the mediation of Notch signals, and L3MBTL3, a methyllysine reader for which deletions are observed in medulloblastoma. We demonstrated that L3MBTL3 is part of a molecular mechanism linking the KDM1A demethylase to Notch signal modulation. We hypothesize that malfunction of this molecular mechanism may contribute to the previously suggested tumor suppressor role of L3MBTL3 in medulloblastoma. In a survival analysis using our L3mbtl3 KO mouse in combination with a genetically engineered mouse model of medulloblastoma, we validated our hypothesis that L3mbtl3 is a tumor suppressor in this disease context. Our discovery provides insights into the role of the L3MBTL3 in medulloblastoma that could be harnessed in the future for the therapeutic benefit of medulloblastoma patients.
Letter by Romaguera et al Regarding Article, “Newer Generation Ultrathin Strut Drug-Eluting Stents Versus Older Second-Generation Thicker Strut Drug-Eluting Stents for Coronary Artery Disease: Meta-Analysis of Randomized Trials”
Authors: Rafael Romaguera, Josep Gomez-Lara, Joan Antoni Gomez-Hospital
Journal: Circulation (2019)
Lower Risk of Hepatocellular Carcinoma With Tenofovir vs Entecavir in Patients With Chronic Hepatitis B
Authors: Hao Zhang, Wenting Zeng
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
The regulation and role of prostaglandin biosynthesis in cultured bovine glomerular endothelial cells.
Authors: K Nitta, M S Simonson, M J Dunn
Journal: Journal of the American Society of Nephrology (1991)

The experiments described in this article were designed to investigate the regulation of, and functional response to, prostaglandin (PG) synthesis in cultured bovine glomerular endothelial cells. Glomerular endothelial cells in culture synthesized PGE2 much greater than PGF2 alpha greater than thromboxane A2 greater than PGI2 in the presence of 30 microM arachidonate. Basal levels of PGE2 synthesis in these cells were one sixth less than that of bovine mesangial cells. PGE2 synthesis was time dependent and required the continuous presence of serum. Moreover, PGE2 synthesis was regulated by phospholipase A2 as shown by ionomycin-stimulated PGE2 accumulation as well as by bradykinin- and thrombin-stimulated PGE2 accumulation. Even though acidic fibroblast growth factor and heparin were required to support glomerular endothelial cell growth in culture, these agents downregulated PGE2 synthesis. PG endoperoxide synthase activity, as shown by arachidonate-stimulated PGE2 accumulation, also regulated PGE2 synthesis. PGE2 and PGF2 alpha, as well as thromboxane A2 and PGI2 mimetics (1 microM) evoked mitogenesis in quiescent glomerular endothelial cells. PGE2 and PGF2 alpha were most potent, and threshold doses of these PG were 10 nM. These data suggest that glomerular endothelial cells are similar to other microvascular endothelial cells in their regulation of PG synthesis and that, under physiological conditions, the proliferation of glomerular endothelial cells might be regulated by PG in an autocrine or paracrine fashion.
Abstract P3-01-06: Correlation of disseminated or circulating tumor cells with the OncotypeDX recurrence score
Authors: SE Tevis, C Hall, S Meas, R Hwang, A Lucci
Journal: Cancer Research (2019)

Abstract Background: New biomarkers continue to emerge to predict the risk of recurrence in women with early stage breast cancer. A high OncotypeDX Recurrence Score (RS)® has been found to be associated with worse disease-free and overall survival in patients with early stage breast cancer. Similarly, circulating tumor cells (CTCs, blood) and disseminated tumor cells (DTCs, bone marrow) have prognostic value in patients with breast cancer. We sought to evaluate the association between high RS and CTCs and DTCs. Methods: We evaluated patients with hormone receptor positive, HER2 negative, node-negative invasive breast cancer from a prospective database from 1/2005 to 1/2017. RS was classified based on the new TAILORx study cutoff points as low (&amp;lt;11), intermediate (11-25), and high (&amp;gt;25). CTCs were assessed using CellSearch. For DTCs cytospin specimens of bone marrow aspirates, enriched for epithelial cells by density gradient separation, were immunostained using a pancytokeratin cocktail of antibodies, including AE1/AE3, CAM5.2, MNF116, cytokeratin 8 (CK8), and CK18. CTCs and DTCs were considered to be positive if one or more CTCs or DTCs were identified, respectively. Chi square analyses were utilized to evaluate for a relationship between OncotypeDX RS and CTCs or DTCs. Statistical analyses were performed in SPSS version 24 with p value &amp;lt;0.05 considered significant. Results: Two hundred and thirty patients meeting the above criteria were identified from a prospective database, of which 106 had OncotypeDX testing results. Of the patients with available OncotypeDX data, 93 patients had CTC results and 60 patients had DTC results. CTCs were detected in the blood of 18/93 (19.4%) patients, while DTCs were detected in the bone marrow of 20/60 (33.3%) patients. Patients with high RS were not more likely to have CTCs as compared with patients who had low or intermediate RS (16.7% vs 19.8%, p=0.801). Similarly, high RS was not associated with the detection of DTCs, with DTCs present in 44.4% of patients with high RS, compared with 31.4% of patients with low or intermediate RS (p=0.443). In the subgroup of patients ≤50 years of age no associations were found between high RS and CTCs (p=0.720) or DTCs (p=0.151). Conclusions: High OncotypeDX RS did not correlate with CTCs in the blood or DTCs in the bone marrow in our study. Citation Format: Tevis SE, Hall C, Meas S, Hwang R, Lucci A. Correlation of disseminated or circulating tumor cells with the OncotypeDX recurrence score [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-01-06.
Medicaid Expansion and Birth Outcomes
Authors: Howard Bauchner, Karen Joynt Maddox
Journal: JAMA (2019)

Clare C. Brown, PhD, MPH; Jennifer E. Moore, PhD, RN; Holly C. Felix, PhD, MPA; M. Kathryn Stewart, MD, MPH; T. Mac Bird, PhD, MS; Curtis L. Lowery, MD; J. Mick Tilford, PhD
Comparison of the Effects of Four Types of Human Mesenchymal Stromal Cells and Fibroblasts on Primary Human Hepatocyte Functions to Improve the Outcome of Hepatocyte Transplantation
Authors: Ella Hubber, Anil Dhawan, Charlotte Lee, Joanna Tang, Emer Fitzpatrick, Audrey Varin, Valeria Iansante, Celine Filippi
Journal: Hepatology (2018)
RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1
Authors: Christopher P. Mill, Warren Fiskus, Courtney D. DiNardo, Yimin Qian, Kanak Raina, Kimal Rajapakshe, Dimuthu Perera, Cristian Coarfa, Tapan M. Kadia, Joseph D. Khoury, Dyana T. Saenz, David N. Saenz, Anuradha Illendula, Koichi Takahashi, Steven M. Kornblau, Michael R. Green, Andrew P. Futreal, John H. Bushweller, Craig M. Crews, Kapil N. Bhalla
Journal: Blood (2019)
De Subitaneis Mortibus
Authors: THOMAS N. JAMES
Journal: Circulation (1974)

In eight cases of scleroderma heart disease studied at necropsy special attention was paid to the cardiac conduction system and the coronary arteries. Six of the eight patients died suddenly, and all had some form of electrical instability of the heart. Distinct morphological abnormalities were present in the sinus node, atrioventricular (A-V) node and His bundle of every case, with sclerotic destruction of the sinus node being particularly striking in four of the hearts. Widespread lesions of the small coronary arteries (less than 1 mm diameter) were present in the ventricular myocardium, the sinus node artery and the A-V node artery. These lesions included mural and intimal fibrosis, endothelial proliferation, medial hyperplasia, fibrinoid necrosis and platelet-fibrin clots. The large coronary arteries were conspicuously normal or minimally diseased except in one case, and in that example there was no myocardial disease attributable to the single large coronary lesion found. It is concluded that arrhythmias and conduction disturbances are an integral component of the clinical picture of scleroderma heart disease, that this is associated with structural abnormalities in the centers of impulse formation and conduction, and that widespread narrowing lesions of the small coronary arteries (but not the major trunks) are important as a basis for fibrotic and degenerative changes throughout the heart. Some components of the fibrosis, particularly in the sinus node, seem disproportionate and suggest that both microvascular and primary collagen abnormalities contribute to the pathogenesis of scleroderma heart disease.
MRI Assessment of Treatment Response in HIV‐associated NAFLD: A Randomized Trial of a Stearoyl‐Coenzyme‐A‐Desaturase‐1 Inhibitor (ARRIVE Trial)
Authors: Veeral H. Ajmera, Edward Cachay, Christian Ramers, Irine Vodkin, Shirin Bassirian, Seema Singh, Neeraj Mangla, Richele Bettencourt, Jeannette L. Aldous, Daniel Park, Daniel Lee, Jennifer Blanchard, Adrija Mamidipalli, Andrew Boehringer, Saima Aslam, Olof Dahlqvist Leinhard, Lisa Richards, Claude Sirlin, Rohit Loomba
Journal: Hepatology (2019)

Aramchol, an oral stearoyl‐coenzyme‐A‐desaturase‐1 inhibitor, has been shown to reduce hepatic fat content in patients with primary nonalcoholic fatty liver disease (NAFLD); however, its effect in patients with human immunodeficiency virus (HIV)–associated NAFLD is unknown. The aramchol for HIV‐associated NAFLD and lipodystrophy (ARRIVE) trial was a double‐blind, randomized, investigator‐initiated, placebo‐controlled trial to test the efficacy of 12 weeks of treatment with aramchol versus placebo in HIV‐associated NAFLD. Fifty patients with HIV‐associated NAFLD, defined by magnetic resonance imaging (MRI)–proton density fat fraction (PDFF) ≥5%, were randomized to receive either aramchol 600 mg daily (n = 25) or placebo (n = 25) for 12 weeks. The primary endpoint was a change in hepatic fat as measured by MRI‐PDFF in colocalized regions of interest. Secondary endpoints included changes in liver stiffness using magnetic resonance elastography (MRE) and vibration‐controlled transient elastography (VCTE), and exploratory endpoints included changes in total‐body fat and muscle depots on dual‐energy X‐ray absorptiometry (DXA), whole‐body MRI, and cardiac MRI. The mean (± standard deviation) of age and body mass index were 48.2 ± 10.3 years and 30.7 ± 4.6 kg/m 2 , respectively. There was no difference in the reduction in mean MRI‐PDFF between the aramchol group at –1.3% (baseline MRI‐PDFF 15.6% versus end‐of‐treatment MRI‐PDFF 14.4%, P = 0.24) and the placebo group at –1.4% (baseline MRI‐PDFF 13.3% versus end‐of‐treatment MRI‐PDFF 11.9%, P = 0.26). There was no difference in the relative decline in mean MRI‐PDFF between the aramchol and placebo groups (6.8% versus 1.1%, P = 0.68). There were no differences in MRE‐derived and VCTE‐derived liver stiffness and whole‐body (fat and muscle) composition analysis by MRI or DXA. Compared to baseline, end‐of‐treatment aminotransferases were lower in the aramchol group but not in the placebo arm. There were no significant adverse events. Conclusion : Aramchol, over a 12‐week period, did not reduce hepatic fat or change body fat and muscle composition by using MRI‐based assessment in patients with HIV‐associated NAFLD (clinicaltrials.gov ID:NCT02684591).
mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency
Authors: Jingsong Cao, Ding An, Mikel Galduroz, Jenny Zhuo, Shi Liang, Marianne Eybye, Andrea Frassetto, Eishi Kuroda, Aki Funahashi, Jordan Santana, Cosmin Mihai, Kerry E. Benenato, E. Sathyajith Kumarasinghe, Staci Sabnis, Timothy Salerno, Kimberly Coughlan, Edward J. Miracco, Becca Levy, Gilles Besin, Joshua Schultz, Christine Lukacs, Lin Guey, Patrick Finn, Tatsuhiko Furukawa, Paloma H. Giangrande, Takeyori Saheki, Paolo G.V. Martini
Journal: Molecular Therapy (2019)

Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options.
Global Health Spending and Development Assistance for Health
Authors: Joseph L. Dieleman, Angela E. Micah, Christopher J. L. Murray
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal