tbuckley/cabot-search huggingface dataset:
Low-Flow, Low-Gradient Aortic Stenosis With Preserved Ejection Fraction: Still a Challenging Condition⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Helmut Baumgartner
Journal: Journal of the American College of Cardiology (2012)
CSIG-16. SEXUAL DIMPORHISM IN IRON ACQUISITION IN GLIOBLASTOMA
Authors: Bhavyata Pandya, Becky Slagle-Webb, Darya Nesterova, Brad Zacharia, Justin Lathia, Joshua Rubin, Michael Berens, Jill S Barnholtz-Sloan, James Connor
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most aggressive brain cancer. Sex differences in incidence and clinical outcomes have been reported, however, our knowledge of contributing mechanisms is limited. Iron acquisition is key to robust tumor growth. Upregulation of Transferrin (Tf, iron transport protein)/Transferrin receptor (TfR) is found in multiple different cancers. We have identified H-ferritin (FTH1) as involved in iron transport and explore its uptake in GBM in this study. We interrogated iron uptake in a syngeneic orthotopic mouse model (GL261 cells) using male and female mice. After the tumors were established, radioactive 125I labeled Tf and FTH1 proteins were injected retro-orbitally in the mice. After 24 hours, tumors were removed, homogenized and analyzed for Tf and FTH1 uptake. There was a significant difference in Tf uptake into the tumor versus matched non-tumor tissue in both males and females and the uptake in the tumors was 1.5-fold higher in males than females. There was no significant difference in FTH1 uptake between male and female tumors nor between tumor and matched non-tumor brain tissue. Binding analyses were performed on homogenized samples of human male and female GBM tissue samples using 125I labeled Tf and FTH1. Tumors from males had increased binding of both proteins compared to tumors from females. We next queried the TCGA database and found in females, high TfR expression was associated with poor survival but not in males. TCGA database revealed a robust expression of Tim1, a putative receptor for FTH1, but its expression did not relate to survival. In summary, this study demonstrates FTH1 binding to GBMs and sexual dimorphism in iron acquisition via Tf and survival.
DIPG-73. SENESCENCE ASSOCIATED SECRETORY PHENOTYPE AS A MECHANISM OF RESISTANCE AND THERAPEUTIC VULNERABILITY IN BMI1 INHIBITOR TREATED DIPG
Authors: Ilango Balakrishnan, Etienne Danis, Angela Pierce, Krishna Madhavan, Dong Wang, Nathan Dahl, Sanford Bridget, Diane K Birks, Nate Davidson, Dennis S Metselaar, Hans Neel, Andrew Donson, Andrea Griesinger, Hiroaki Katagi, Trinka Vijmasi, Ismail Sola, Irina Alimova, Susan Fosmire, Esther Hulleman, Natalie J Serkova, Rintaro Hashizume, Cynthia Hawkins, Angel Montero Carcaboso, Nalin Gupta, Ken Jones, Nicholas Foreman, Adam Green, Rajeev Vibhakar, Sujatha Venkataraman
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse intrinsic pontine gliomas (DIPGs) driven by mutations in the histone 3 (H3) gene (H3K27M) are aggressive pediatric brain tumors for which there is no curative therapy. METHODS To identify novel therapeutic targets we performed a high throughput drug screen combined with an epigenetically targeted RNAi screen using H3K27M and H3.3 WT DIPG cells. RESULTS Chemical and genetic depletion of BMI1 in vitro resulted in inhibition of clonogenicity and cell self-renewal consistent with previous studies. We show for the first time that clinically relevant BMI1 inhibitors attenuates growth of orthotopic DIPG xenografts as measured by MRI and prolong survival in vivo. We found that BMI1 inhibition drives phenotypic cellular senescence and that the senescent cells were able reactivate to form new neurospheres in vitro and tumor growth in vivo. RNA-seq, ChIP-Seq and immuno-proteomic analysis revealed that the senescent cells induced the expression of the Senescence Associated Secretory Phenotype (SASP) cytokines by increasing occupancy of activated histone marks at SASP factor promoters. The SASP results in increased expression of anti-apoptotic BH3 proteins including BCLxl, and BCL2. Treatment of the PTC028 treated senescent DIPG cells with BH3 mimetics induces apoptosis and clears the senescent cells. Combining BH3 mimetics with BMI1 inhibition attenuates tumor growth in vivo synergistically and significantly prolongs survival of DIPG bearing mice compared to BMI1 inhibition alone. CONCLUSION These data inform the current trial of BMI1 inhibition as a monotherapy and predict the need for adding BH3 mimetics to achieve efficacy.
American College of Surgeons Efforts in Support of Value-Based Metrics
Authors: Heidi Nelson, Clifford Y. Ko, David B. Hoyt
Journal: JAMA Oncology (2020)

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
RBIO-05. MITOTIC ENRICHMENT AS AN EFFICIENT STRATEGY TO RADIOSENSITIZE GLIOBLASTOMA
Authors: Mark C de Gooijer, Paul L G Slangen, Ceren H Çitirikkaya, Hilal Çolakoğlu, Amal El Ouazani, Ronak Shah, Gerben R Borst, Olaf van Tellingen
Journal: Neuro-Oncology (2020)

Abstract Their location and highly aggressive nature renders glioblastoma (GBM) among the most deadly and devastating of human malignancies. Despite extensive treatment involving surgery and adjuvant chemo-radiotherapy, the prognosis is still dismal and novel treatment strategies are urgently needed. Of all existing adjuvant therapies, radiotherapy contributes the most to extending the median overall survival. Increasing the efficacy of existing radiotherapeutic regimens is therefore a logical avenue to improve the survival of GBM patients. We have developed a novel radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that especially mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied hyperfractionated radiotherapy regimens. We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. Most importantly, this tubulin inhibitor efficiently radiosensitizes a range of preclinical GBM models in vitro and in vivo, including GSC models, and significantly improves survival, but only in a mitotic enrichment setup when given 6-8 hours prior to radiotherapy to allow accumulation in mitosis. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other mitotic targets and different intra- and extracranial cancer models representing several diseases for which radiotherapy is a mainstay treatment. In parallel, we are preparing a phase 0 trial to demonstrate induction of mitotic enrichment in human GBM.
Angiotensin-Converting Enzyme Inhibitor Therapy at the Time of Coronary Artery Bypass Surgery: When a Friend Turns Mean-Spirited⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: David S. Bach
Journal: Journal of the American College of Cardiology (2009)
NEK9, a novel effector of IL-6/STAT3, regulates metastasis of gastric cancer by targeting ARHGEF2 phosphorylation
Authors: Guofang Lu, Siyuan Tian, Yi Sun, Jiaqiang Dong, Na Wang, Jiaoxia Zeng, Yongzhan Nie, Kaichun Wu, Ying Han, Bin Feng, Yulong Shang
Journal: Theranostics (2020)

Rationale: Inflammatory stimuli from the tumor microenvironment play important roles in cancer progression. However, the mechanism of promotion of cancer metastasis by inflammation in gastric cancer (GC) is poorly understood. Methods: The roles of NEK9 were validated via loss-of-function and gain-of-function experiments in vitro and in an animal model of metastasis. Cytoskeletal reorganization-associated molecules were detected by GST pull-down. The regulation of ARHGEF2 by NEK9 was investigated by phosphoproteomics analysis, immunoprecipitation (IP) and in vitro kinase assay. The transcriptional regulation of miR-520f-3p was studied using luciferase reporter and chromatin immunoprecipitation (ChIP). The expression of these proteins in GC tissues was examined by immunohistochemistry. Results: NEK9 directly regulates cell motility and RhoA activation in GC. The phosphorylation of ARHGEF2 by NEK9 is the key step of this process. NEK9 is a direct target of miR-520f-3p, which is transcriptionally suppressed by IL-6-mediated activation of STAT3. A decrease in miR-520f-3p leads to the amplification of IL-6/STAT3 by targeting GP130. A simultaneous elevation of the levels of NEK9, GP130 and p-STAT3 was confirmed in the lymph nodes and distant metastases. An increase in NEK9, GP130 and STAT3 is associated with reduced overall survival of GC patients. Conclusion: This study demonstrates that activation of STAT3 by IL-6 transcriptionally suppresses miR-520f-3p and diminishes the inhibitory effects of miR-520f-3p on NEK9 and GP130. An increase in GP130 enhances this signaling, and NEK9 directly influences cell motility and RhoA activation by targeting the phosphorylation of ARHGEF2. Targeting the IL-6-STAT3-NEK9 pathway may be a new strategy for GC treatment.
Medical Genetic Studies of the Amish.
Journal: Annals of Internal Medicine (1978)

This compact book, designed to be a practical guide to statistical methods used in medical genetics, certainly meets its goal.Chapters on estimation of gene frequencies, population genetic structure, multifactorial inheritance, genetic linkage, twin studies, recurrence risks for counseling, disease association, parental age, birth order, and changes in disease frequency all contain clearly stated, useful insights into what often has been presented in a manner difficult for the nonexpert to understand.If there is a weak area, it is the chapter on segregation analysis.Analysis of autosomal dominant inheritance, contrary to the impression given, is often as complex as that of recessive inheritance due to decreased penetrance and ascertainment bias.The method of multiple incomplete ascertainment, by far the most common method in practice, is dealt with very superficially.In several areas of the book estimates are presented as if they are parameters, and in the section on multifactorial inheritance the transition between qualitative and quantitative traits is not as clear as it might be.This small book, however, has much to recommend it and since publication in 1976 has received complimentary reviews in The British Medical Journal, Journal of Medical Genetics and The Lancet.I would second these compliments which included the adjectives useful, enjoyable, compact and lucid.The book will be very helpful for individuals seeking to understand or contribute to literature related to mathematical aspects of medical genetics but who are not ultrasophisticated in the methodology.It will also serve as a supplement to courses in methodology.Congratulations to Dr. Emery for a needed and well written addition to the literature in human genetics.
EPCO-34. CLINICAL AND GENETIC EVOLUTION OF EPENDYMOMA
Authors: Zhong-ping Chen, Jing Wang, Qun-ying Yang, Jing Zeng
Journal: Neuro-Oncology (2020)

Abstract Ependymomas are glial brain tumors accounting for approximately 2~3% of all primary tumors in central nervous system (CNS), and 12% of all pediatric intracranial tumors. To better understand the evolution process of ependymomas, we studied the clinical, pathological and genetic development of a rare girl case with repeatedly recurrent ependymoma. This girl was diagnosed as anaplastic ependymoma at age of 9 years old, and experienced 7 times tumor relapse and received 9 times surgeries but finally ceased at19 years old with multiregional recurrences. The pathological characteristics, radiographic images and therapeutic strategies of the patient were all retrieved. Molecular markers confirmed the diagnosis based on the updated WHO guideline for CNS tumors. Whole-genome sequencing (WGS) was performed to elucidate the landscape of mutation signatures and to identify potential driver mutations along the tumor progression. The seven tumor specimens showed a highly branched evolutionary pattern. There were six gene mutations found in 5 of the 7 specimens (PCDHA4, PCDHA8, SEC14L6, SETD2, RIOK2, and SLCO2A1) and three in 6 of 7 the samples (RYR1, SNX25, DSC2). Strikingly, there was one gene, ADGRL3, which was found to be consistently mutated in the entire disease progression process. Our findings therefore suggest that ADGRL3 might play roles in the disease progression of ependymoma patient.
All Surgeons Are in This Together
Authors: Elizabeth C. Wick, Julie Ann Sosa
Journal: JAMA Surgery (2020)

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 Surgery 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 Surgery journal
IMMU-40. IMPROVING OUTCOMES IN OLDER ADULTS WITH GLIOBLASTOMA BY REVERSING AGE-RELATED CHANGES OF THE CENTRAL NERVOUS SYSTEM
Authors: Erik Ladomersky, Lijie Zhai, Lakshmi Bollu, April Bell, Kristen Lauing, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2020)

Abstract De novo glioblastoma (GBM) represents ≥ 90% of all GBM diagnoses and has a median age of onset at 65 years old. Because of its preponderance during advanced age, we investigated the mortality rate of older adult C57BL/6 (WT) mice with CT-2A glioma. Strikingly, we discovered a significant decrease of overall survival among animal subjects depleted for both CD4+ and CD8+ T cells as compared to the group treated with IgG control antibodies. This negative effect of lymphopenia only applied to older adults. We next questioned which of the major T cell subsets contribute to this effect and determined that the depletion of CD4+ T cells significantly decreased overall survival as compared to IgG control or CD8+ T cell-depleting antibodies (n=12/group; p&amp;lt; 0.01). We previously found increased immunosuppressive IDO levels in the mouse and human brain during advanced age. Although 78–86 week old WT mice have no survival benefit after triple combination immunotherapy, age-matched IDOKO mice have an impressive increase in median and overall survival – despite both groups being treated with a pharmacologic IDO enzyme inhibitor. Since IDO is potently-induced by proinflammatory cytokines, we hypothesized that a potential mechanism for the increased IDO during advanced age is associated with an accumulation of senescent cells in the brain with a proinflammatory secretory phenotype. To investigate this, 80 week old mice with intracranial GL261 were treated with (i) vehicle with IgG antibodies, (ii) the senolytic drugs dasatanib and quercetin, (iii) whole brain radiation, anti-PD-1 mAb, and IDO enzyme inhibitor, or (iv) the 5 agent combination. Only animal subjects treated with the 5 agent cocktail showed a significant increase in long-term survival in a subset of mice (n=12–15/group; p&amp;lt; 0.01). These results suggest that optimization of senescent cell eradication treatment may be particularly beneficial to older patients with GBM treated with immunotherapy.
LGG-52. BINIMETINIB IN CHILDREN WITH PROGRESSIVE OR RECURRENT LOW-GRADE GLIOMA NOT ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1: INITIAL RESULTS FROM A MULTI-INSTITUTIONAL PHASE II STUDY
Authors: Nathan Robison, Jasmine Pauly, Jemily Malvar, Sharon Gardner, Jeffrey Allen, Tobey MacDonald, Dolly Aguilera, Patricia Baxter, Anne Bendel, Lindsay Kilburn, Sarah Leary, Daniel Bowers, Kathleen Dorris, Karen Gauvain, Elizabeth Alva, Kenneth Cohen, Kellie Nazemi, Yi Juin Tan, Ashley Margol, Girish Dhall, Tena Rosser, Tom Davidson, Ashley Plant, Nicole Ullrich, Pratiti Bandopadhayay, Nathalie Agar, Keith Ligon, Richard Sposto, Karen Wright, Mark Kieran
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (LGG). Binimetinib is an orally bioavailable MEK1/2 inhibitor found to have significant central nervous system penetration in a preclinical model. OBJECTIVE The primary objective of this multi-institutional open-label phase II study was to assess preliminary efficacy of binimetinib in progressive pediatric LGG. The study included strata for both neurofibromatosis type I (NF1) and non-NF1 associated tumors, as well as a target validation (surgical) stratum. NF1 and surgical strata remain open to enrollment and will be reported separately. METHODS Children aged 1–18 years with previously treated recurrent or progressive LGG were eligible. The dose of binimetinib was 32 mg/m2/dose twice daily. Partial and minor responses were defined, respectively, as 50% and 25% decrease in maximal two-dimensional measurements. RESULTS Fifty-seven eligible patients without NF1, median age 8 years, were enrolled and began treatment; 26 were female; 28 had documented KIAA1549-BRAF fusion. Eleven patients discontinued drug in the first year due to toxicity, and an additional 27 required dose reduction. The most common drug-attributable grade 3 toxicities included creatine kinase elevation (n=9 patients), rash (n=8), and truncal weakness (n=8). Truncal weakness improved or resolved with dose reduction or cessation. Grade 4 toxicities included creatine kinase elevation (n=2) and transient colitis (n=1). Of 44 patients with preliminary response data available, 22 (50%) showed a minor (n=7) or partial (n=15) response. CONCLUSION Binimetinib is active, with manageable toxicities, in children without NF1 with progressive LGG.
適合非血縁ドナーからの造血細胞移植における抗ヒトTリンパ球免疫グロブリンありおよびなしでの標準的移植片対宿主病予防後の長期転帰:無作為化対照試験の最終結果【Powered by NICT】
Authors: Finke Juergen, Schmoor Claudia, Bethge Wolfgang Andreas, Ottinger Hellmut, Stelljes Matthias, Volin Liisa, Heim Dominik, Bertz Hartmut, Grishina Olga, Socie Gerard
Journal: The Lancet Haematology (2017)
Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer
Authors: Deanna N. Edwards, Verra M. Ngwa, Ariel L. Raybuck, Shan Wang, Yoonha Hwang, Laura C. Kim, Sung Hoon Cho, Yeeun Paik, Qingfei Wang, Siyuan Zhang, H. Charles Manning, Jeffrey C. Rathmell, Rebecca S. Cook, Mark R. Boothby, Jin Chen
Journal: Journal of Clinical Investigation (2020)

Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially serving as a therapeutic intervention strategy. Here, we report that there is an inverse correlation between glutamine metabolic genes and markers of T cell-mediated cytotoxicity in human basal-like breast cancer (BLBC) patient data sets, with increased glutamine metabolism and decreased T cell cytotoxicity associated with poor survival. We found that tumor cell-specific loss of glutaminase (GLS), a key enzyme for glutamine metabolism, improved antitumor T cell activation in both a spontaneous mouse TNBC model and orthotopic grafts. The glutamine transporter inhibitor V-9302 selectively blocked glutamine uptake by TNBC cells but not CD8+ T cells, driving synthesis of glutathione, a major cellular antioxidant, to improve CD8+ T cell effector function. We propose a "glutamine steal" scenario, in which cancer cells deprive tumor-infiltrating lymphocytes of needed glutamine, thus impairing antitumor immune responses. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC.
Differential Diagnosis for Electrocardiography Challenge—Reply
Authors: Ravi Choxi, Todd Teigeler, Richard Shepard
Journal: JAMA Internal Medicine (2020)

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 Internal Medicine 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 Internal Medicine journal