tbuckley/cabot-search huggingface dataset:
Bile‐Derived Organoids From Patients With Primary Sclerosing Cholangitis Recapitulate Their Inflammatory Immune Profile
Authors: Carol J. Soroka, David N. Assis, Leina S. Alrabadi, Scott Roberts, Laura Cusack, Ariel B. Jaffe, James L. Boyer
Journal: Hepatology (2018)

Primary sclerosing cholangitis (PSC) is a heterogeneous and progressive fibroinflammatory cholangiopathy with no known etiology or effective treatment. Studies of PSC are limited due to difficulty in accessing the cholangiocyte, the small percentage of these cells in the liver, instability of in vitro culture systems, and reliance on samples from end‐stage disease. Here, we demonstrate that stem cells can be isolated from the bile of PSC patients undergoing endoscopic retrograde cholangiopancreatography earlier in their clinical course and maintained long term in vitro as three‐dimensional (3D) organoids that express a biliary genetic phenotype. Additionally, bile‐derived organoids (BDOs) can be biobanked and samples obtained longitudinally over the course of the disease. These BDOs express known cholangiocyte markers including gamma glutamyl transferase, cytokeratin 19, epithelial cellular adhesion molecule, cystic fibrosis transmembrane conductance regulator, and anion exchanger 2. RNA sequence analysis identified 39 genes whose expression differed in organoids from PSC patients compared to non‐PSC controls, including human leukocyte antigen DM alpha chain and chemokine (C‐C motif) ligand 20 (CCL20), immune‐related genes previously described in genome‐wide association studies of PSC. Incubation of these BDOs with interleukin 17A or tumor necrosis factor alpha led to an immune‐reactive phenotype with a significant increase in secretion of proinflammatory mediators, including CCL20, a T‐cell chemoattractant. Conclusion : This study demonstrates that bile can be used as a source of biliary‐like cells that can be maintained long term in vitro as 3D organoids; these BDOs retain features of cholangiopathies, including the ability to react to inflammatory stimuli by secreting chemokines and propagating an immune‐reactive phenotype reflective of the pathogenesis of these diseases; thus, BDOs represent a platform for the study of the pathogenesis and therapy of cholangiopathies, particularly PSC.
Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity
Authors: Chien-Chun Steven Pai, Donald M. Simons, Xiaoqing Lu, Michael Evans, Junnian Wei, Yung-hua Wang, Mingyi Chen, John Huang, Chanhyuk Park, Anthony Chang, Jiaxi Wang, Susan Westmoreland, Christine Beam, Dave Banach, Diana Bowley, Feng Dong, Jane Seagal, Wendy Ritacco, Paul L. Richardson, Soumya Mitra, Grace Lynch, Pete Bousquet, John Mankovich, Gillian Kingsbury, Lawrence Fong
Journal: Journal of Clinical Investigation (2018)

While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte–associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4–binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1–/– mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2–bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti-CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities.
Abstract 17313: Radiation Exposure of Patients During Chronic Total Occlusion Percutaneous Coronary Intervention: Update From a Contemporary Multicenter Registry
Authors: Judit Karacsonyi, Dimitri Karmpaliotis, Khaldoon Alaswad, Jeffrey W Moses, Ajay Kirtane, Manish Parikh, Ziad Ali, David E Kandzari, Nicholas Lembo, William Lombardi, Anthony Doing, Barry Uretsky, James Choi, Farouc A Jaffer, Mitul Patel, Ehtisham Mahmud, Robert W Yeh, Santiago Garcia, Peter Tajti, Jose R Martinez-Parachini, Aris Karatasakis, Barbara Danek, Georgios E Christakopoulos, Bavana V Rangan, Imre Ungi, Craig A Thompson, Subhash Banerjee, Emmanouil S Brilakis
Journal: Circulation (2017)

Introduction: Radiation-related complications are an important concern for chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods: Patient radiation dose and its associatio...
SAT0086 Evaluation of diagnostic performance of magnetic resonance imaging (MRI) and ultrasound (US) toward early rheumatoid arthritis from nagasaki early arthritis cohort
Authors: A. Takatani, M. Tamai, N. Ohki, Y. Nakashima, Y. Endo, S. Tsuji, T. Shimizu, M. Umeda, S. Fukui, R. Sumiyoshi, A. Nishino, T. Koga, S.-Y. Kawashiri, N. Iwamoto, T. Igawa, K. Ichinose, K. Arima, H. Nakamura, T. Origuchi, S. Sato, M. Uetani, A. Kawakami
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> We previously reported that the presence of autoantibodies, magnetic resonance imaging (MRI) bone oedema, ultrasound (US) power Doppler (PD) &amp;x2267; grade 2 articular synovitis are indispensable markers to predict the development of RA from undifferentiated arthritis whereas combination analysis used by the above variables, focusing on very early phase of arthritis, remains to be done in our cohort. <h3>Objectives</h3> To investigate and re-confirm the diagnostic performance of autoantibodies, MRI findings and US findings toward early RA from NAGASAKI EARLY ARTHRITIS COHORT. <h3>Methods</h3> One hundred and three patients, suffering arthralgia less than 6 months and examined by both MRI and US of wrist and finger joints, were selected from NAGASAKI EARLY ARTHRITIS COHORT dating from September 2009 to August 2017. US were evaluated by synovitis score of semi-quantitative manner by gray-scale (GS) and power Doppler (PD) proposed from EULAR. In MRI, synovitis, bone oedema and bone erosion were assessed by the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system (RAMRIS). After univariate analysis, multivariate analysis was employed to clarify the diagnostic predictors of early RA. <h3>Results</h3> Median of age was 60 years and that of symptomatic duration was 2 months. Female was 68.9%, positive rate of RF was 64.7% and that of ACPA was 47.1%. Total GS score was 4.0, total PD score 2.0, MRI synovitis score 3.0, MRI bone oedema score 0, MRI bone erosion score 0. Seventy patients were diagnosed as early RA during follow-up periods. A univariate analysis showed ACPA, CRP, MMP-3, fulfilment of 2010 ACR/EULAR criteria, MRI synovitis score, MRI bone oedema score, total GS score, total PD score and PD &amp;x2267; grade 2 articular synovitis were associated with early RA. Multivariate analysis revealed ACPA and PD &amp;x2267; grade 2 articular synovitis at any joints were independent predictors toward diagnosis of early RA. <h3>Conclusions</h3> Our present study re-confirms the importance of ACPA, PD &amp;x2267; grade 2 articular synovitis and MRI bone oedema, especially the former two, to predict the development of early RA from undifferentiated arthritis patients. <h3>Disclosure of Interest</h3> None declared
A Single Center Retrospective Study of Real World Relapsed/Refractory DLBCL Patients Eligible for CAR T-Cell Therapy: Patient Characteristics and Outcomes
Authors: Neil Bailey, John M. Pagel, William Bensinger, Livia Hegerova, Raya Mawad, Michael Milder, Jennie Szeto, Ngan Trinh, Tenzin Tsomo, Paul Wisniewski, Clarisse M. Zayas, Krish Patel
Journal: Blood (2018)
A Smarter War on Drugs
Authors: Howard K. Koh, R. Gil Kerlikowske, Michael P. Botticelli
Journal: JAMA (2018)

Still, Ferdinands said, "we do feel that it would be prudent not to encourage a shift of vaccination into the July and August time frame."Schaffner echoed Ferdinands."Most of us would look askance at people getting vaccinated in August" or early September, he said."If you're 22 years old and in robust health, maybe that doesn't matter."But a frail 72-year-old with diabetes might want to wait until October to get a flu shot, Schaffner said.Carving that message into stone in the form of practice guidelines is another matter.
Abstract 13841: Aortic and Pulmonary Dissections in Women With Turner Syndrome
Authors: Angela T Yetman, Megan Wilde, Jonathan W Cramer, Lois Starr, Jennifer Sanmann, Mary Murray
Journal: Circulation (2017)

Introduction: While aortic dissection in women with Turner syndrome (TS) has been well reported, other vascular dissections, including pulmonary artery (PA) dissections, have not been noted. In 200...
Health Care, Family, and Community Factors Associated with Mental, Behavioral, and Developmental Disorders and Poverty Among Children Aged 2–8 Years — United States, 2016
Authors: Robyn A. Cree, Rebecca H. Bitsko, Lara R. Robinson, Joseph R. Holbrook, Melissa L. Danielson, Camille Smith, Jennifer W. Kaminski, Mary Kay Kenney, Georgina Peacock
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Childhood mental, behavioral, and developmental disorders (MBDDs) are associated with adverse outcomes that can persist into adulthood (1,2). Pediatric clinical settings are important for identifying and treating MBDDs (3). Early identification and treatment of MBDDs can promote healthy development for all children (4), especially those living in poverty who are at increased risk for MBDDs (3,5) but might have reduced access to care (6). CDC analyzed data from the 2016 National Survey of Children's Health (NSCH) on MBDDs, risk factors, and use of federal assistance programs (e.g., Supplemental Nutrition Assistance Program [SNAP]) to identify points to reach children in poverty. In line with previous research (3,6), compared with children in higher-income households, those in lower-income households more often had ever received a diagnosis of an MBDD (22.1% versus 13.9%), and less often had seen a health care provider in the previous year (80.4% versus 93.8%). Among children living below 200% of the federal poverty level (FPL) who did not see a health care provider in the previous year, seven of 10 were in families receiving at least one public assistance benefit. Public assistance programs might offer collaboration opportunities to provide families living in poverty with information, co-located screening programs or services, or connection to care.
Abstract 12727: Prediction of Occurrence of Adverse Events Using Right Ventricular End Diastolic and Systolic Volume Measurements on ECG-Gated 320 Slice CT in Subjects With Chronic Thromboembolic Pulmonary Hypertension. A Study With a Median of 23 Months Follow-Up
Authors: Koya Ozawa, Nobusada Funabashi, Hiroyuki Takaoka, Nobuhiro Tanabe, Koichiro Tatsumi, Yoshio Kobayashi
Journal: Circulation (2014)

Introduction: Right ventricular (RV) volume measurements may predict short term prognosis in subjects with chronic pulmonary thromboembolic pulmonary hypertension (CTEPH). Aim: To predict occurrence of adverse events (AE) in subjects with CTEPH, we quantitative measured three dimensional RV end-diastolic (RVEDV) and end-systolic volume (RVESV) in these subjects using ECG gated enhanced 320 slice CT. Methods: 29 CTEPH subjects (9 males, 58 ± 15 years) underwent retrospective ECG gated 320 slice CT (Aquilion one, Toshiba Medical). To obtain not only images of the whole heart including RV and coronary arteries, but also images of the pulmonary artery, all CT scans were obtained using a double volume conventional scan with retrospective ECG gating with a 0.5 mm slice thickness and tube current dose modulation. We injected 60 ml of contrast material (350 mgI/ml) at 3.5 ml/s, followed by injection of a saline-to-contrast material mixture (40 ml contrast material at 2.0 ml/s and 30 ml saline at 1.5 ml/s), follow...
Split First Dose Administration of Daratumumab for the Treatment of Patients with Multiple Myeloma (MM): Clinical Pharmacology and Population Pharmacokinetic (PK) Analyses
Authors: Xu Steven Xu, Philippe Moreau, Saad Z. Usmani, Sagar Lonial, Andrzej Jakubowiak, Albert Oriol, Amrita Krishnan, Joan Bladé, Melody Luo, Yu-Nien Sun, Liping Zhang, William Deraedt, Ming Qi, Jon Ukropec, Pamela L Clemens
Journal: Blood (2018)
Early Loss of Histone H2B Monoubiquitylation Alters Chromatin Accessibility and Activates Key Immune Pathways That Facilitate Progression of Ovarian Cancer
Authors: Jagmohan Hooda, Marián Novak, Matthew P. Salomon, Chikako Matsuba, Romela I. Ramos, Emily MacDuffie, Melissa Song, Michelle S. Hirsch, Jenny Lester, Vinita Parkash, Beth Y. Karlan, Moshe Oren, Dave S. Hoon, Ronny Drapkin
Journal: Cancer Research (2018)

Recent insights supporting the fallopian tube epithelium (FTE) and serous tubal intraepithelial carcinomas (STIC) as the tissue of origin and the precursor lesion, respectively, for the majority of high-grade serous ovarian carcinomas (HGSOC) provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Here, we investigate the role of the E3 ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis and report that heterozygous loss of RNF20 defines the majority of HGSOC tumors. At the protein level, H2Bub1 was lost or downregulated in a large proportion of STIC and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in the development of serous ovarian carcinoma. Knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to enhance cell migration and clonogenic growth of FTE cells. To investigate the mechanisms underlying these effects, we performed ATAC-seq and RNA-seq in RNF20 knockdown FTE cell lines. Loss of RNF20 and H2Bub1 was associated with a more open chromatin conformation, leading to upregulation of immune signaling pathways, including IL6. IL6 was one of the key cytokines significantly upregulated in RNF20- and H2Bub1-depleted FTE cells and imparted upon these cells an enhanced migratory phenotype. These studies provide mechanistic insight into the observed oncogenic phenotypes triggered by the early loss of H2Bub1. SIGNIFICANCE: Loss of RNF20 and H2Bub1 contributes to transformation of the fallopian tube epithelium and plays a role in the initiation and progression of high-grade serous ovarian cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/760/F1.large.jpg.
Cytoreductive Nephrectomy in Metastatic Renal Cell Cancer
Authors: Primo N. Lara, Christopher P. Evans
Journal: JAMA Oncology (2018)

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Carboplatin (CB) combined with oral or intravenous (IV) etoposide (ET) for advanced extra-pulmonary (EP) poorly differentiated (PD) neuroendocrine carcinoma (NEC): Real-world findings from two European neuroendocrine tumour society centres of excellence
Authors: M. Frizziero, F. Spada, A. Lamarca, Z. Kordatou, J. Barriuso, C. Nuttall, M.G. McNamara, R. Hubner, W. Mansoor, P. Manoharan, N. Fazio, J.W. Valle
Journal: Annals of Oncology (2018)
Phase 1/1b Study of the Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, As Monotherapy or in Combination with Cytarabine for the Treatment of Relapsed/Refractory AML and Advanced MDS with TP53 Wild-Type
Authors: David A Sallman, Uma Borate, Elizabeth H. Cull, William B. Donnellan, Rami S. Komrokji, Ulrich G. Steidl, Maria M Corvez, Marie Payton, D. Allen Annis, Dawn Pinchasik, Manuel Aivado, Amit Verma
Journal: Blood (2018)
NGR-derived isoDGR is a natural recognition motif of the RGD-binding site of αvβ3 integrin
Authors: Andrea Spitaleri, Silvia Mari, Flavio Curnis, Catia Traversari, Renato Longhi, Claudio Bordignon, Angelo Corti, Gian-Paolo Rizzardi, Giovanna Musco
Journal: Cancer Research (2008)

1976  NGRhTNF is a vascular targeting agent in phase II clinical development exploiting a tumor homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumors, where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I5) generates isoDGR, an αvβ3 integrin binding motif that regulates endothelial cell adhesion and proliferation (Curnis et al JBC 2006, 281:36466). In the present work, we analyze the structure of CisoDGRC (isoDGR), a cyclo-peptide that mimicks the FN-I5 site, as well as those of NGR, RGD or DGR-containing cyclo-peptides, by NMR and molecular dynamics (MD) studies on each peptide. These studies indicate that isoDGR has a high degree of macrocycle flexibility, yielding to a significantly greater conformational heterogeneity as compared to the other cyclo-peptides. The resulting conformers have been docked onto the αvβ3 crystallographic structure in its “RGD-bound” conformation (Xiong et al Science 2002, 296:151). Docking experiments along with MD studies on each complex peptide-receptor show that isoDGR favorably interacts with the RGD-binding site of αvβ3, both recapitulating canonical RGD/αvβ3 contacts and establishing additional polar interactions. Among these, the N-terminal cysteine flanking the isoDGR sequence points towards the binding site, contributing to receptor recognition. In contrast, NGR and DGR motives lack the fundamental pharmacophoric requirements for high receptor affinity. Consistently, MD studies do not show over time stable interactions of NGR and DGR with the αvβ3-biding site. Finally, our structural models are in accord with experimental results obtained in cell adhesion and binding assays, indicating that isoDGR and RGD, but not NGR and DGR, peptides bind to αvβ3 with similar affinity, and inhibit cell adhesion of endothelial cells.Overall, these data provide the structural basis to define isoDGR as a new natural recognition motif of αvβ3, while indicate that NGR sequence lacks the pharmacophoric features to bind αvβ3. The results also contribute to explain the functional differences of fibronectin NGR and isoDGR sequences. In this context, we argue that NGR→isoDGR transition may represent an important physiological mechanism able to work as a molecular timer for activating latent integrin-binding sites in fibronectin, with important patho-physiological implications in development, angiogenesis, inflammation, wound repair and tumor growth.
Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure
Authors: Lena Dorsheimer, Birgit Assmus, Tina Rasper, Christina A. Ortmann, Andreas Ecke, Khalil Abou-El-Ardat, Tobias Schmid, Bernhard Brüne, Sebastian Wagner, Hubert Serve, Jedrzej Hoffmann, Florian Seeger, Stefanie Dimmeler, Andreas M. Zeiher, Michael A. Rieger
Journal: JAMA Cardiology (2018)

<h3>Importance</h3> Somatic mutations causing clonal expansion of hematopoietic cells (clonal hematopoiesis of indeterminate potential [CHIP]) are increased with age and associated with atherosclerosis and inflammation. Age and inflammation are the major risk factors for heart failure, yet the association of CHIP with heart failure in humans is unknown. <h3>Objective</h3> To assess the potential prognostic significance of CHIP in patients with chronic heart failure (CHF) owing to ischemic origin. <h3>Design, Setting, and Participants</h3> We analyzed bone marrow–derived mononuclear cells from 200 patients with CHF by deep targeted amplicon sequencing to detect the presence of CHIP and associated such with long-term prognosis in patients with CHF at University Hospital Frankfurt, Frankfurt, Germany. Data were analyzed between October 2017 and April 2018. <h3>Results</h3> Median age of the patients was 65 years. Forty-seven mutations with a variant allele fraction (VAF) of at least 0.02 were found in 38 of 200 patients with CHF (18.5%). The somatic mutations most commonly occurred in the genes<i>DNMT3A</i>(14 patients),<i>TET2</i>(9 patients),<i>KDM6A</i>(4 patients), and<i>BCOR</i>(3 patients). Patients with CHIP were older and more frequently had a history of hypertension. During a median follow-up of 4.4 years, a total of 53 patients died, and 23 patients required hospitalization for heart failure. There was a significantly worse long-term clinical outcome for patients with either<i>DNMT3A</i>or<i>TET2</i>mutations compared with non-CHIP carriers. By multivariable Cox proportional regression analysis, the presence of somatic mutations within<i>TET2</i>or<i>DNMT3A</i>(HR, 2.1; 95% CI, 1.1-4.0;<i>P</i> = .02, for death combined with heart failure hospitalization) and age (HR, 1.04; 95% CI, 1.01-1.07 per year;<i>P</i> = .005) but not a history of hypertension remained independently associated with adverse outcome. Importantly, there was a significant dose-response association between VAF and clinical outcome. <h3>Conclusions and Relevance</h3> Our data suggest that somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes<i>TET2</i>and<i>DNMT3A</i>, may be significantly associated with the progression and poor prognosis of CHF. Future studies will have to validate our findings in larger cohorts and address whether targeting specific inflammatory pathways may be valuable for precision medicine in patients with CHF carrying specific mutations encoding for CHIP.