tbuckley/cabot-search huggingface dataset:
Visit-to-Visit Blood Pressure Variability, Coronary Atheroma Progression, and Clinical Outcomes
Authors: Donald Clark, Stephen J. Nicholls, Julie St John, Mohamed B. Elshazly, Haitham M. Ahmed, Haitham Khraishah, Steven E. Nissen, Rishi Puri
Journal: JAMA Cardiology (2019)

<h3>Importance</h3> Visit-to-visit blood pressure variability (BPV) is associated with cardiovascular events, but mechanisms and therapeutic implications underlying this association are not well understood. <h3>Objective</h3> To examine the association of intraindividual BPV, coronary atheroma progression, and clinical outcomes using serial intravascular ultrasonography. <h3>Design, Setting, and Participants</h3> Post hoc patient-level analysis of 7 randomized clinical trials conducted from 2004 to 2016 involving 3912 patients in multicenter, international, clinic-based primary and tertiary care centers. Adult patients with coronary artery disease who underwent serial intravascular ultrasonography in the setting of a range of medical therapies were included. Data were analyzed between November 2017 and March 2019. <h3>Exposures</h3> Visit-to-visit BPV measured using intraindividual standard deviation over 3, 6, 12, 18, and 24 months. <h3>Main Outcomes and Measures</h3> Percent atheroma volume (PAV) progression and major adverse cardiovascular events (defined as death, myocardial infarction, stroke, urgent revascularization for acute coronary syndrome, and hospitalization for unstable angina). <h3>Results</h3> Of 3912 patients, the mean (SD) age was 58 (9) years, 1093 (28%) were women, and 3633 (93%) were white . Continuous change in PAV was significantly associated with systolic BPV (β, .049; 95% CI, 0.021-0.078;<i>P</i> = .001), diastolic BPV (β, .031; 95% CI, 0.002-0.059;<i>P</i> = .03), and pulse pressure variability (β, .036; 95% CI, 0.006-0.067;<i>P</i> = .02), without a signal for differential effect greater than or less than a mean BP of 140/90 mm Hg. The PAV progression as a binary outcome was significantly associated with systolic BPV (odds ratio, 1.09; 95% CI, 1.01-1.17;<i>P</i> = .02) but not diastolic BPV (odds ratio, 1.04; 95% CI, 0.97-1.11;<i>P</i> = .30) or pulse pressure variability (odds ratio, 1.03; 95% CI, 0.96-1.10;<i>P</i> = .47). Survival curves revealed a significant stepwise association between cumulative major adverse cardiovascular events and increasing quartiles of systolic BPV (Kaplan-Meier estimates for quartiles 1-4: 6.1% vs 8.5% vs 10.1% vs 12.0%, respectively; log-rank<i>P</i> &lt;.001). These distinct stepwise associations were not seen with diastolic BPV or pulse pressure variability. <h3>Conclusions and Relevance</h3> Greater BPV, particularly systolic BPV, is significantly associated with coronary atheroma progression and adverse clinical outcomes. These data suggest maintaining stable blood pressure levels may be important to further improve outcomes in patients with coronary disease.
SAT-432-The CT1 multi-parametric MRI value is more sensitive and reliable than transient elastography for the non-invasive monitoring of intra-hepatic inflammation/fibrosis response to DAA therapy in CHC patients
Authors: Antonio Salvati, Nicola Martini, Andy Mckay, Barbara Coco, Piero Colombatto, Gabriele Ricco, Filippo Oliveri, Veronica Romagnoli, Francesco Faita, Ferruccio Bonino, Dante Chiappino, Maurizia Rossana Brunetto
Journal: Journal of Hepatology (2019)
Intestinal and hepatic microbiota changes associated with chronic ethanol administration in mice
Authors: Sena Bluemel, Lirui Wang, Claire Kuelbs, Kelvin Moncera, Manolito Torralba, Harinder Singh, Derrick E. Fouts, Bernd Schnabl
Journal: Gut Microbes (2019)

Alcohol-induced liver disease is closely related to translocation of bacterial products and bacteria from the intestine to the liver. However, it is not known whether bacterial translocation to the liver depends on certain intestinal microbiota changes that would predispose bacteria to translocate to the liver. In this study, we investigated the microbiota in the jejunum, ileum, cecum, feces and liver of mice subjected to chronic ethanol feeding using a Lieber DeCarli diet model of chronic ethanol feeding for 8 weeks. We demonstrate that chronic ethanol administration changes alpha diversity in the ileum and the liver and leads to compositional changes especially in the ileum. This is largely driven by an increase in gram-negative phyla – the source of endotoxins. Moreover, gram-negative Prevotella not only increased in the mucus layer of the ileum but also in liver samples. These results suggest that bacterial translocation to the liver might be associated with microbiota changes in the distal gastrointestinal tract.
A novel human Fc-optimized ICAM-1/CD54 antibody (MSH-TP15e) with potent anti-myeloma activity in vitro and in vivo.
Authors: Matthias Peipp, Martin Gramatzki, Renate Burger, Katja Klausz, Christian Kellner, Andreas Guenther
Journal: Journal of Clinical Oncology (2015)

e19533 Background: Despite the introduction of stem cell transplantation and novel agents (proteasome inhibitors, immunomodulatory drugs) for treatment of multiple myeloma (MM), a substantial number of patients are still in need for better disease control. A growing number of monoclonal antibodies with different targets have proven effective in cancer therapy. In MM CD38 and CD319 antibodies entered clinical development. But there is still a need to develop additional target structures as well as potent formats for antibody-based therapy in this disease. Methods: With MSH-TP15 a novel ICAM-1/CD54 antibody was isolated from synthetic scFv phage display libraries with a cellular screening strategy. The scFv clone was selected from a panel of phage antibodies based on its favorable binding profile to various MM cell lines and patient-derived CD138-positive malignant plasma cells. The antigen recognized by MSH-TP15 was identified as CD54. The isolated scFv was used to generate fully human IgG1 antibody variants. MSH-TP15-derived antibodies were analyzed for their capacity to kill MM cells in vitro (chromium release assay, inhibition of proliferation) and in a xenograft tumor model with INA-6, a plasma cell line raised in our laboratory. Results: Different engineered Fc domains were evaluated to unravel the mechanisms of cytotoxic action triggered by MSH-TP15 and to enhance distinct effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC). MSH-TP15e did not induce direct growth inhibition by apoptosis as reported for another ICAM-1 antibody, probably due to different antigen binding capabilities. However, this Fc-optimized MSH-TP15e variant significantly triggered ADCC against various cell lines or freshly isolated myeloma cells by recruitment of natural killer cells. Importantly, this antibody completely inhibited tumor growth in vivo in the INA-6 xenograft MM model. Conclusions: Apparently due to its unique binding capability and the engineered Fc-part MSH-TP15e exerts potent anti-myeloma activity in vivo and may be therapeutic in MM.
Correlation between S-1 treatment outcome and expression of biomarkers for refractory thymic carcinoma.
Authors: Yusuke Okuma, Yukio Hosomi, Shingo Miyamoto, Yoshiro Nakahara, Tatsuru Okamura, Tsunekazu Hishima
Journal: Journal of Clinical Oncology (2015)

e18565 Background: Thymic carcinoma is a rare cancer with minimal evidence of a survival benefit following chemotherapy. An oral fluoropyrimidine of S-1, however, is the recommended active cytotoxic chemotherapy agent for refractory thymic carcinoma based on a case series, whereas sunitinib or everolimus are recommended as molecular-targeted agents based on Phase II trials. We retrospectively investigated the efficacy of S-1 for refractory thymic carcinoma and performed a biomarker analysis. Methods: We assessed the clinicopathological variables of 14 consecutive patients who underwent S-1 for refractory thymic carcinoma and correlated the clinical outcomes with potential biomarkers using paraffin-embedded cancer tissues of eight patients in the cohort. Results: A total of 178 thymic malignancies were identified, of whom 14 patients included 12 cases of squamous cell carcinoma, one lymphoepithelioma-like carcinoma, and one undifferentiated carcinoma. Six patients exhibited a partial response (42.9%: 95% confidence interval [CI], 21.4–67.4) and the disease control rate was 85.7% (60.0–96.0%). After a median follow-up of 24.2 months, the median progression-free survival was 8.1 months (range, 2.6–12.2 months), and median overall survival was 30.0 months (range, 6.2–41.9 months). No significant correlation between biomarker expression and response was noted. However, thymidine synthase (TS)/dihydropyrimidine dehydrogenase and TS/orotate phosphoribosyltransferase were observed. Conclusions: S-1 for refractory thymic carcinoma offered clinical activity and achieved an 85% disease control rate. Although the biomarkers did not correlate with clinical outcome, the study results showed efficacy of S-1 as a cytotoxic chemotherapy for refractory thymic carcinoma, which warrants future investigation.
The Childhood Solid Tumor Network: A St. Jude Initiative.
Authors: Elizabeth Stewart, Cori Bradley, Sara Michele Federico, Asa Karlstrom, Andras Sablauer, Alberto S. Pappo, Michael A. Dyer
Journal: Journal of Clinical Oncology (2015)

e21022 Background: Pediatric solid tumors are rare and basic research that focuses on the mechanisms of tumor development provide the best hope for new therapies. However, limited access to applicable resources has hindered developmental scientists. To support basic research on pediatric solid tumors, we have established the Childhood Solid Tumor Network (CSTN). Methods: We established comprehensive datasets and validated biological specimens and animal models for basic research which include genomic and other molecular data, cell lines, patient-derived orthotopic xenografts, and genetically engineered mouse models of childhood solid tumors. Over 50 xenograft models of various solid tumors have been characterized using histology, electron microscopy, gene expression profiling, single nucleotide polymorphism microarrays, whole genome sequencing, exome sequencing, RNA-seq and DNA methylation. High-throughput drug screening of primary cultures derived from xenografts was performed as well as plasma and tumor pharmacokinetics. All data, samples, and animal models are shared freely through an online request form without obligation to collaborate. Results: Since its inception, there have been 195 requests from 81 investigators (40 internal, 41 external) that have resulted in nearly 1200 distributed samples. The investigators represent 25 different institutions spanning the continents of Asia, Australia, Europe, and North America. Samples have expanded the field through publications including those of genomic characterization, clonal evolution, high-throughput screening, and preclinical efficacy testing of novel therapeutics for pediatric solid tumors. Conclusions: TheCSTN has developed a representative diverse panel of pediatric solid tumors that are easily accessible to the research community. We hope the CSTN will emerge as the central nexus for sharing of data, expertise, and resources for basic and translational research in pediatric solid tumors.
Evaluation of the Interrater Reliability of End-of-Life Medical Orders in the Physician Orders for Life-Sustaining Treatment Form
Authors: Gustavo Bigaton Lovadini, Fernanda Bono Fukushima, Joao Francisco Lindenberg Schoueri, Roberto dos Reis, Cecilia Guimarães Ferreira Fonseca, Jahaira Jeanainne Casanova Rodriguez, Cauana Silva Coelho, Adriele Ferreira Neves, Aniela Maria Rodrigues, Marina Almeida Marques, Alessandro Ferrari Jacinto, Karen Harrison Dening, Rick Bassett, Alvin H. Moss, Karl E. Steinberg, Edison Iglesias de Oliveira Vidal
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Despite its spread in much of the United States and increased international interest, the Physician Orders for Life-Sustaining Treatment (POLST) paradigm still lacks supporting evidence. The interrater reliability of the POLST form to translate patients' values and preferences into medical orders for care at the end of life remains to be studied. <h3>Objective</h3> To assess the interrater reliability of the medical orders documented in POLST forms. <h3>Design, Setting, and Participants</h3> This cross-sectional study was conducted in a public university hospital in southeastern Brazil. Two independent researchers interviewed the same patients or decision-making surrogates (n = 64) during a single episode of hospitalization within a time frame of 1 to 7 days. Eligible participants were hospitalized adults aged 21 years or older who were expected to remain hospitalized for at least 4 days and whose attending physician responded no to the question, Would I be surprised if this patient died in the next year? Data collection occurred between November 1, 2015, and September 20, 2016, and first data analyses were performed on October 3, 2016. <h3>Main Outcomes and Measures</h3> Interrater reliability as measured by κ statistics. <h3>Results</h3> Of the 64 participants interviewed in the study, 53 (83%) were patients and 11 (17%) were surrogates. Patients' mean (SD) age was 64 (14) years, and 35 patients (55%) and 8 surrogates (73%) were women. Overall, in 5 cases (8%), disagreement in at least 1 medical order for life-sustaining treatment was found in the POLST form, changing from the first interview to the second interview. The κ statistic for cardiopulmonary resuscitation was 0.92 (95% CI, 0.80-1.00); for level of medical intervention, 0.89 (95% CI, 0.76-1.00); and for artificially administered nutrition, 0.92 (95% CI, 0.83-1.00). <h3>Conclusions and Relevance</h3> The high interrater reliability of the medical orders in POLST forms appears to offer further support for this advance care planning paradigm; in addition, the finding that this interrater reliability was not 100% underscores the need to ensure that patients or their surrogates have decision-making capacity and to confirm that the content of POLST forms accurately reflects patients' current treatment preferences.
TCTAP A-099 Comparing Radiation Dose and Contrast Usage Between Biplane and Single Plane Imaging for Coronary Angiography and Coronary Angioplasty
Authors: Lawrence Cabilatazan Fronda, Hui Lin Felicia Huang, Ma. Louise Dianne Sasoy, Joyce Pooi Wan Lee, Syed Saqib Imran, Michael Mao-Chen Liang, Zhan Yun Lim
Journal: Journal of the American College of Cardiology (2019)
PS-042-Interventional targeting of cyclin E1 during hepatocarcinogenesis limits stem cell traits and hepatic myeloid cell homing and attenuates cancer progression
Authors: Roland Sonntag, Marlene Kohlhepp, Antje Mohs, Ute Haas, Daniela Lambertz, Frank Tacke, Christian Trautwein, Christian Liedtke
Journal: Journal of Hepatology (2019)
Abstract 190: Mesenchymal Stromal Cells (MSCs) Regulate Neutrophil Extracellular Traps (NETs) Through Adenosine
Authors: Rebecca Levit, Eric Shin, LanFang Wang, Kai Xu
Journal: Circulation Research (2017)

Background: NETs released by neutrophils may be an important component of inflammation in MI/R. NETs consist of extruded DNA, histone, and other chromatin components and are pro-thrombotic and pro-inflammatory. MSCs as a cell therapy for MI/R may act by modulating the innate immune response including NETs. MSCs convert pro-inflammatory ATP into anti-inflammatory adenosine (ADO) via CD 73, a 5’ ectonucleotidase. Objective: To investigate the role of MSCs in regulating NETs through ADO production. Methods: Neutrophils were freshly isolated from peripheral blood of healthy donors. Human bone marrow derived MSCs were grown under standard conditions. Neutrophils were stimulated to produce NETs by PMA (1 μg/ml) and quantified by Sytox green fluorescence. Some neutrophils were also treated with MSCs or ADO. Results: Neutrophils treated with PMA had a 1.9±0.19, (p&lt;0.05) fold increase in NET formation as quantified by Sytox green florescence. Treatment with MSCs in 1:10 ratio prevented increased NET production in response to PMA (1.02±0.12 fold increase). Pretreatment of MSCs with a CD 73 inhibitor APCP reduced their ability to prevent NET formation in some donors (1.62±0.10). ADO decreased NET formation in a dose dependent manner. Conclusion: MSCs may inhibit NET formation through ADO signaling and could be an important mechanism of MSC anti-inflammatory effects in MI/R. Future studies will investigate the ability of MSCs to inhibit NET formation in MI/R.
SAT-473-Transition to the era of direct-acting antiviral changes in the prognosis of patients with hepatitis C virus-related hepatocellular carcinoma
Authors: Yoshifumi Miura, Sadahisa Ogasawara, Yoshihiko Ooka, Kazufumi Kobayashi, Susumu Maruta, Hiroaki Kanzaki, Kengo Kanayama, Takahiro Maeda, Soichiro Kiyono, Yuko Kusakabe, Masato Nakamura, Eiichiro Suzuki, Tomoko Saito, Shingo Nakamoto, Shin Yasui, Akinobu Tawada, Tetsuhiro Chiba, Makoto Arai, Tatsuo Kanda, Hitoshi Maruyama, Naoya Kato
Journal: Journal of Hepatology (2019)
The Emergence of Population Health in US Academic Medicine
Authors: Marc N. Gourevitch, Lesley H. Curtis, Maureen S. Durkin, Angela Fagerlin, Annetine C. Gelijns, Richard Platt, Belinda M. Reininger, Judith Wylie-Rosett, Katherine Jones, William M. Tierney
Journal: JAMA Network Open (2019)

In response to rapidly growing interest in population health, academic medical centers are launching department-level initiatives that focus on this evolving discipline. This trend, with its potential to extend the scope of academic medicine, has not been well characterized.To describe the emergence of departments of population health at academic medical centers in the United States, including shared areas of focus, opportunities, and challenges.This qualitative study was based on a structured in-person convening of a working group of chairs of population health-oriented departments on November 13 and 14, 2017, complemented by a survey of core characteristics of these and additional departments identified through web-based review of US academic medical centers. United States medical school departments with the word population in their name were included. Centers, institutes, and schools were not included.Departments were characterized by year of origin, areas of focus, organizational structure, faculty size, teaching programs, and service engagement. Opportunities and challenges faced by these emerging departments were grouped thematically and described.Eight of 9 population health-oriented departments in the working group were launched in the last 6 years. The 9 departments had 5 to 97 full-time faculty. Despite varied organizational structures, all addressed essential areas of focus spanning the missions of research, education, and service. Departments varied significantly in their relationships with the delivery of clinical care, but all engaged in practice-based and/or community collaboration. Common attributes include core attention to population health-oriented research methods across disciplines, emphasis on applied research in frontline settings, strong commitment to partnership, interest in engaging other sectors, and focus on improving health equity. Tensions included defining boundaries with other academic units with overlapping areas of focus, identifying sources of sustainable extramural funding, and facilitating the interface between research and health system operations.Departments addressing population health are emerging rapidly in academic medical centers. In supporting this new framing, academic medicine affirms and strengthens its commitment to advancing population health and health equity, to improving the quality and effectiveness of care, and to upholding the social mission of medicine.
GS-13-Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in cwith PEG-interferon Alpha 2a in patients with chronic HBV/HDV co-infection
Authors: Heiner Wedemeyer, Katrin Schöneweis, Pavel O. Bogomolov, Natalia Voronkova, Vladimir Chulanov, Tatyana Stepanova, Birgit Bremer, Lena Allweiss, Maura Dandri, Jürgen Burhenne, Walter-Emil Haefeli, Sandra Ciesek, Ulf Dittmer, Alexander Alexandrov, Stephan Urban
Journal: Journal of Hepatology (2019)
The Fragility Index—<i>P</i> Values Reimagined, Flaws and All—Reply
Authors: Christopher J. Tignanelli, Lena M. Napolitano
Journal: JAMA Surgery (2019)

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FRI-444-VTX-803 AAV-mediated correction of progressive familiar intrahepatic cholestasis type 3 in a clinically relevant mouse model
Authors: Nicholas DWeber, Leticia Odriozola, Javier Martínez-García, Veronica Ferrer, Anne Douar, Bernard Bénichou, Cristian Smerdou, Gloria González-Aseguinolaza
Journal: Journal of Hepatology (2019)
Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma
Authors: Yan Song, Paul M. C. Park, Lei Wu, Arghya Ray, Sarah Picaud, Deyao Li, Virangika K. Wimalasena, Ting Du, Panagis Filippakopoulos, Kenneth C. Anderson, Jun Qi, Dharminder Chauhan
Journal: Leukemia (2019)