tbuckley/cabot-search huggingface dataset:
Abstract 2805: DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of an ovarian cancer mouse model
Authors: Meghan Travers, Stephen Brown, Matthew Dunworth, Cassandra Holbert, Robert Casero, Cynthia Zahnow
Journal: Cancer Research (2019)

Abstract Although ovarian cancer has a low incidence rate encompassing roughly 1% of all new cancers, it remains the most deadly gynecologic malignancy. Our lab has designed a novel combination therapy which combines a DNA methyl transferase inhibitor (DNMTi) and ornithine decarboxylase inhibitor that together, alter the tumor microenvironment to inhibit ovarian tumor growth. Previous work has demonstrated that the DNMTi 5-Azacytidine (AZA) activates type I interferon signaling (Li, 2014, Chiappinelli, 2015) to increase IFNγ+ T cells and NK cells and reduce the percentage of macrophages and myeloid derived suppressor cells (MDSCs) in the tumor microenvironment (Stone, 2017). To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor may decrease activity of MDSCs through inhibition of arginase. Immunocompetent C57Bl/6 mice were injected with syngeneic mouse ovarian surface epithelial (MOSE) tumor cells (ID8-VEGF-Defensin) and subsequently treated with AZA, DFMO, or combination AZA+DFMO. After several weeks, mice developed hemorrhagic ascites that was drained, processed and stained for cell-surface markers and analyzed by flow cytometry to identify T cells, NK cells, and macrophages. We found that in vivo AZA, DFMO, and AZA+DFMO significantly increased survival in mice, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK Cells compared to vehicle. The combination therapy had a striking increase in survival when compared to single agent treatment; however, the difference in recruited lymphocytes was less striking. Instead, combination therapy led to the most dramatic decrease in immunosuppressive cells such as M2 polarized macrophages and increase in tumor-killing M1 macrophages. Using a CSF1R blocking antibody, we found that depleting macrophages in this model reduced the efficacy of AZA+DFMO treatment, and resulted in fewer M1 macrophages in the tumor microenvironment. We thus conclude that our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival. We hypothesize that this treatment regimen could have a widespread impact on macrophage-rich tumors in general, and plan to test this hypothesis in additional tumor models. Citation Format: Meghan Travers, Stephen Brown, Matthew Dunworth, Cassandra Holbert, Robert Casero, Cynthia Zahnow. DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of an ovarian cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2805.
Engineered Anti-CRISPR Proteins for Precision Control of CRISPR-Cas9
Authors: Felix Bubeck, Mareike D. Hoffmann, Zander Harteveld, Sabine Aschenbrenner, Andreas Bietz, Judith Notbohm, Christina Stengl, Jan Mathony, Max C. Waldhauer, Laura Dietz, Kathleen Boerner, Julia Fakhiri, Carolin Schmelas, Dirk Grimm, Bruno E. Correia, Roland Eils, Dominik Niopek
Journal: Molecular Therapy (2019)
Hemoglobin-A1c level to predict for clinical outcomes in patients with pancreatic cancer.
Authors: Katherine Y. Fan, Avani Satish Dholakia, Aaron Tyler Wild, Zheng Su, Amy Hacker-Prietz, Rachit Kumar, Mary Hodgin, Charles C. Hsu, Dung T. Le, Ana De Jesus-Acosta, Luis A. Diaz, Daniel A. Laheru, Ralph H. Hruban, Elliot K. Fishman, Todd D. Brown, Timothy M. Pawlik, Christopher Lee Wolfgang, Phuoc T. Tran, Joseph M. Herman
Journal: Journal of Clinical Oncology (2013)

4039 Background: An association between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDA) has long been recognized. While long-standing DM may be a risk factor for developing PDA, new-onset DM may be a manifestation of the cancer. Here we assess the role of an objective and quantifiable measure of glucose intolerance, hemoglobin-A1c (HbA1c), in predicting clinical outcomes in PDA. Methods: HbA1c values were prospectively collected on 656 consecutive patients presenting to the Johns Hopkins Pancreas Multidisciplinary Cancer Clinic from 2009-2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsy-confirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Patients with prior treatment for PDA or a history of DM greater than a 1-year were excluded. Univariate Cox regression analyses and multivariable proportional hazards models were used to identify poor prognostic factors for overall survival. Results: Of 284 patients included, 44 had benign disease, 62 R-PDA, 115 BL-PDA, and 63 M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had higher HbA1c values on average at presentation than patients with BPD (6.1% vs. 5.6%, p&lt;0.001). There was a trend towards higher HbA1c at presentation in patients with advanced PDA (BL and M) compared to patients with R-PDA (6.2% vs. 5.9%, p=0.100); moreover, the proportion of patients with HbA1c levels in the diabetic range (&gt;6.4%) increased with more advanced stage of disease. Among patients with PDA (n=240), univariate analyses showed HbA1c≥6.5, age≥65, ECOG≥1, CA19-9&gt;90, tumor size &gt;3cm, and advanced stage to be significantly associated with inferior survival (all HR&gt;1, p&lt;0.05). After multivariate analysis with backward elimination, all of the above factors except for tumor size &gt;3cm remained in the model for inferior survival. Conclusions: HbA1c level at presentation appears to correlate with disease stage and, moreover, to predict for survival among all stages of PDA. Patients with PDA have significantly higher HbA1c levels at presentation than patients with BPD. This study highlights the potential utility of HbA1c as a screening tool and prognostic factor.
Impact on survival of adjuvant chemotherapy following chemo-radiotherapy and surgery in locally advanced, non-metastatic rectal adenocarcinoma: a retrospective analysis among 331 patients
Authors: M. Sondag, M. Nguimpi Tambou, C. Schumacher, J. Reimund, L. Serfaty, B. Duclos
Journal: Annals of Oncology (2019)
Abstract 1745: Ku70 suppresses alternative end-joining in G1-arrested progenitor B cells
Authors: Richard L. Frock, Vipul Kumar, Zhouyi Liang, Jeff Zurita, Zhou Du, Sherry G. Lin, Cristian Boboila, Frederick W. Alt
Journal: Cancer Research (2019)

Abstract Classical non-homologous end-joining (C-NHEJ) repairs DNA double-stranded breaks (DSBs) throughout interphase but is thought to predominate in G1-phase when homologous recombination is unavailable. Complexes containing the Ku70/80 ("Ku") and XRCC4/Ligase4 core C-NHEJ factors are required, respectively, for sensing and joining DSBs. While such factors are exclusively required for joining RAG-initiated DSBs during V(D)J recombination in G1-phase lymphocyte progenitors, cycling cells deficient for core C-NHEJ factors join chromosomal DSBs by alternative end-joining (A-EJ) pathways. Restriction of V(D)J recombination to C-NHEJ has been attributed to RAG-mediated exclusion of A-EJ; however, it remains unclear whether A-EJ is similarly excluded from more general DSBs in G1. Here, we report that Ku actively and robustly suppresses A-EJ of both RAG- and Cas9-mediated DSBs in G1-arrested progenitor B cell lines. Thus, while Cas9/gRNA DSBs remain as free broken ends in Ligase4-deficient G1-arrested progenitor B cells, deletion of Ku70 in Ligase4-deficient cells restores DSB re-joining and translocation to levels observed in Ku70-deficient counterparts. Correspondingly, while V(D)J recombination is abrogated in Ligase4-deficient lines, V(D)J-like joining occurs in Ku70-deficient and Ku70/Ligase4-double-deficient lines through a translocation-based A-EJ mechanism. We conclude that in G1, Ligase4-deficient progenitor B cells are functionally end-joining deficient due to a complete Ku-dependent block in A-EJ. Thus, the differential impacts of Ku deficiency versus XRCC4/Ligase4 deficiency on V(D)J recombination, severity of neuronal apoptosis, and embryonic development, including ability of Ku-deficiency to rescue Ligase4-deficient embryonic lethality, may be explained by Ku-mediated inhibition of A-EJ in the G1 cell cycle phase. Citation Format: Richard L. Frock, Vipul Kumar, Zhouyi Liang, Jeff Zurita, Zhou Du, Sherry G. Lin, Cristian Boboila, Frederick W. Alt. Ku70 suppresses alternative end-joining in G1-arrested progenitor B cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1745.
Annals Graphic Medicine - Dr. Mom: Grand Rounds
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2019)

Web Exclusives2 July 2019Annals Graphic Medicine - Dr. Mom: Grand RoundsFREEGrace E. Farris, MDGrace E. Farris, MDMount Sinai School of Medicine, New York, New York (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G18-0047 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Mount Sinai School of Medicine, New York, New York (G.E.F.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G18-0042.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Icahn School of Medicine at Mount Sinai and chief of hospital medicine at Mount Sinai West hospital in New York, New York. You can view her work at her Web site: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears monthly in Annals Graphic Medicine at Annals.org. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 2 July 2019Volume 171, Issue 1Page: W1-W2KeywordsConflicts of interestDisclosureHospital medicineHospitalists ePublished: 2 July 2019 Issue Published: 2 July 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 1864: Verticillin A causes DNA damage and apoptosis in high grade serous ovarian cancer
Authors: Amrita Salvi, Julia Austin, Daniel Lantvit, Joanna Burdette
Journal: Cancer Research (2019)

Abstract High grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy affecting women worldwide and the fifth most common cause of cancer related deaths among U.S. women. New targeted therapies are needed to prevent HGSOC progression and metastasis related lethality from the disease. The goal of this study was to test the novel natural compound, Verticillin A, for its anticancer properties and mode of action in HGSOC cells. Verticillin A is an epipolythiodioxopiperazine (ETP) alkaloid that is isolated from several terrestrial and marine filamentous fungi and has been shown to be cytotoxic in several cancer cell lines including OVCAR8, OVCAR4 and Kuramochi. Our data indicated that Verticillin A treatment caused cytotoxicity in HGSOC cell lines in a dose-dependent manner. Furthermore, treatment with Verticillin A in HGSOC cell line OVCAR8 and OVCAR4 enhanced apoptosis, which was demonstrated by PARP cleavage and Annexin V/ Propidium iodide staining. To determine whether Verticillin A caused in vivo tumor growth inhibition, OVCAR8-RFP cells were xenografted in mice to form tumors and the mice were treated with Verticillin A. Encapsulated nanoparticles of Verticillin A decreased tumor growth in vivo and had low cytotoxicity compared to the naked drug. RNA-Seq analysis was performed with OVCAR8 cells treated with Verticillin A and the data found an upregulation of apoptosis signaling pathway and oxidative stress response and downregulation of cancer stemness signaling pathways. A proteomic histone profiling performed in OVCAR8 cells indicated that Verticillin A caused epigenetic modifications with global changes in histone methylation and acetylation marks. Thus, our study identifies Verticillin A as a novel epigenetic modifier in ovarian cancer cells and indicates therapeutic potential for treatment of HGSOC. Note: This abstract was not presented at the meeting. Citation Format: Amrita Salvi, Julia Austin, Daniel Lantvit, Joanna Burdette. Verticillin A causes DNA damage and apoptosis in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1864.
Abstract 2456: NetZen: A comprehensive network-based pathway and target discovery platform
Authors: Son Le, Alberto Riva, Changwang Deng, David D. Tran
Journal: Cancer Research (2019)

Abstract BACKGROUND: Success in precision medicine depends on the ability to accurately and rapidly identify master regulators of critical gene subnetworks. To achieve this goal requires a seamless computational target discovery platform that integrates global network visualization with identification of master regulatory subnetworks (MRS) and their key influencers. METHODS: We have created NetZen - a computer cluster-capable computational suite allowing for 1) robust network generation with million edges; 2) network-based MRS identification; 3) hierarchical analysis with automated annotations; and 4) whole-network 3D visualization of all 20,000 genes. To identify cancer MRS, we applied NetZen to expression datasets of tumors and normal tissues, tumor-initiating cells (TICs), non-TIC cancer cells, and normal stem and non-stem cells from TCGA, GEO and internal sources. For validation, we introduced these subnetworks in normal cells to recapitulate TIC phenotypes in vivo or disrupted them in patients-derived TICs and mouse xenografts (PDX). To identify MRS of mortality, we applied NetZen to survival data in TCGA. RESULTS: Networks of 28 human cancers were generated, integrating transcriptomics, microRNAs, proteomics, and clinical data. For cancers with TIC datasets, we identified TIC-specific MRS with clear-cut hierarchy controlling immune surveillance, EMT and developmental functions. Interestingly, in some cancers, the immune subnetwork including immune checkpoints was entirely encompassed in the developmental subnetwork. We present representative validation on glioblastoma TIC (GIC) MRS with features common in other cancers’ TICs. Exogenous introduction of this subnetwork in normal astrocytes forced them to become GICs and form tumors in mice. Disrupting this subnetwork in 10 independent PDXs profoundly blunted tumor growth and prolonged survival. Lastly, we present detailed MRS of mortality analysis of multiple cancer types and identify common pathways directly influencing outcomes. DISCUSSION: NetZen provides a complete solution to big data analysis by effortlessly processing million-edge hierarchical networks with biological insights through automated annotations. The findings that the immune and developmental subnetworks were intimately linked suggest that immune escape by TICs is intrinsic of cellular transformation rather than a product of selection. Lastly, detailed network hierarchy provides a logical roadmap for cancer therapeutic development. Citation Format: Son Le, Alberto Riva, Changwang Deng, David D. Tran. NetZen: A comprehensive network-based pathway and target discovery platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2456.
Abstract 19111: Impact of Diabetes Mellitus on the Hospitalization Costs of Endovascular Stenting for Peripheral Arterial Disease: A Nationwide Analysis Using the National Inpatient Database of 2012-2014
Authors: Xin Wei, Ahmadreza Moradi, Parisa Toosi, Mariam Khandaker, Bing Yue, Sung E Lee, Yuzhou Liu
Journal: Circulation (2017)

Introduction: Peripheral artery disease (PAD) is common and imposes a high risk of major systemic and limb ischemic events and consequently, high healthcare cost. The primary objective of our study...
A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial
Authors: Elias Dakwar, Edward V. Nunes, Carl L. Hart, Richard W. Foltin, Sanjay J. Mathew, Kenneth M. Carpenter, C.J. “Jean” Choi, Cale N. Basaraba, Martina Pavlicova, Frances R. Levin
Journal: American Journal of Psychiatry (2019)

Objective: Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention. Methods: Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout). Results: Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events. Conclusions: A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.
Факторы риска развития кандидоза слизистой оболочки верхнего отдела желудочно-кишечного тракта. Проблема антибиотикотерапии
Authors: I.V. Kushnirenko
Journal: GASTROENTEROLOGY (2019)

Актуальность. По данным литературы, существует ряд факторов, обусловливающих развитие кандидоза верхнего отдела пищеварительного тракта, однако значимость их в формировании заболевания окончательно не определена. Противоречивые данные существуют и касательно антибиотикотерапии как фактора риска у пациентов, не находящихся на лечении в отделении интенсивной терапии. Отсутствуют рекомендации по тактике ведения пациентов после применения антибиотиков. Цель. Определение факторов риска развития орофарингеального кандидоза по величине вклада в риск развития заболевания, а также изучение проблемы антибиотикотерапии и разработка рекомендаций по тактике ведения пациентов. Материалы и методы. Обследованы и проанкетированы 638 пациентов, которые по результатам микробиологического исследования соскоба с языка разделены на группы: 1 группа — 151 пациент с орофарингеальным кандидозом, то есть ІV степенью массивности обсеменения; 2 группа — 327 пациентов с незначительным и умеренным ростом грибов (I, II та III степень массивности обсеменения); 3 группа — 160 лиц с негативным результатом посева (0 степень). Результати. Выявлены существенные различия между группами 1 и 3 по таким факторам риска орофарингеального кандидоза, как прием антибиотиков в течение года, курение, ношение зубных протезов, наличие кандидозного вульвовагинита у женщин, а также сопутствующая патология щитовидной железы и анемия. При сравнении групп 1 и 2 значимыми являются прием антибиотиков в течение года и патология щитовидной железы. Диагностическая чувствительность сформированной на основании полученных данных анкеты — 83,3 %, доверительный интервал (ДИ) 75,9–88,8 %, специфичность — 75,1 %, ДИ 70,7–79,0 %, эффективность модели — 77,0 %, ДИ 73,3–80,4 %. Из 291 пациента, которым назначались антибиотики, у 199 лиц (68,4 %) проведена антифунгальная терапия, однако распределение степеней массивности обсеменения грибами у них отличий не имело. Анализ показал, что дозы, сроки и выбор антифунгального препарата не соответствовали современным международным рекомендациям. Выводы. Применение разработанной с учетом факторов риска развития орофарингеального кандидоза диагностической анкеты позволяет повысить эффективность диагностики. Проведение антибиотикотерапии требует наблюдения за пациентом и после микробиологической верификации диагноза кандидоза — проведения лечения. Оптимальной терапевтической тактикой является применение системных антигрибковых препаратов согласно международным рекомендациям при одновременной коррекции факторов риска, поддающихся модификации.