tbuckley/cabot-search huggingface dataset:
Clonal Hematopoiesis–Driver DNMT3A Mutations Alter Immune Cells in Heart Failure
Authors: Wesley Tyler Abplanalp, Sebastian Cremer, David John, Jedrzej Hoffmann, Bianca Schuhmacher, Maximillian Merten, Michael A. Rieger, Mariuca Vasa-Nicotera, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2020)

Clonal hematopoiesis driven by mutations of DNMT3A (DNA methyltransferase 3a) is associated with increased incidence of cardiovascular disease and poor prognosis of patients with chronic heart failure (HF) and aortic stenosis. Although experimental studies suggest that DNMT3A clonal hematopoiesis-driver mutations may enhance inflammation, specific signatures of inflammatory cells in humans are missing.To define subsets of immune cells mediating inflammation in humans using single-cell RNA sequencing.Transcriptomic profiles of peripheral blood mononuclear cells were analyzed in n=6 patients with HF harboring DNMT3A clonal hematopoiesis-driver mutations and n=4 patients with HF and no DNMT3A mutations by single-cell RNA sequencing. Monocytes of patients with HF carrying DNMT3A mutations demonstrated a significantly increased expression of inflammatory genes compared with monocytes derived from patients with HF without DNMT3A mutations. Among the specific upregulated genes were the prototypic inflammatory IL (interleukin) IL1B (interleukin 1B), IL6, IL8, the inflammasome NLRP3, and the macrophage inflammatory proteins CCL3 and CCL4 as well as resistin, which augments monocyte-endothelial adhesion. Silencing of DNMT3A in monocytes induced a paracrine proinflammatory activation and increased adhesion to endothelial cells. Furthermore, the classical monocyte subset of DNMT3A mutation carriers showed increased expression of T-cell stimulating immunoglobulin superfamily members CD300LB, CD83, SIGLEC12, as well as the CD2 ligand and cell adhesion molecule CD58, all of which may be involved in monocyte-T-cell interactions. DNMT3A mutation carriers were further characterized by increased expression of the T-cell alpha receptor constant chain and changes in T helper cell 1, T helper cell 2, T helper cell 17, CD8+ effector, CD4+ memory, and regulatory T-cell-specific signatures.This study demonstrates that circulating monocytes and T cells of patients with HF harboring clonal hematopoiesis-driver mutations in DNMT3A exhibit a highly inflamed transcriptome, which may contribute to the aggravation of chronic HF.
Personalized Risk-Profiling for Acute Leukemia Patients Undergoing Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation: A Study on Behalf of the Acute Leukemia Working Party of the EBMT
Authors: Joshua A Fein, Roni Shouval, Myriam Labopin, Fabio Ciceri, Emanuele Angelucci, Didier Blaise, Johanna Tischer, William Arcese, Yener Koc, Benedetto Bruno, Jose L. Diez-Martin, Stella Santarone, Simona Sica, Jurjen Versluis, Mohamad Mohty, Arnon Nagler
Journal: Blood (2020)
Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) As a Biomarker of Renal Outcomes in AL Amyloidosis
Authors: Efstathios Kastritis, Ioannis Papassotiriou, Foteini Theodorakakou, Alexandra Margeli, Anastasia Barzteliotou, Eleni Tsiligkeridou, Amalia Andreatou, Despina Fotiou, Magdalini Migkou, Nikolaos Kanellias, Ioanna Dialoupi, Ioannis Ntanasis-Stathopoulos, Panagiotis Malandrakis, Maria Gavriatopoulou, Evangelos Terpos, Meletios A Dimopoulos
Journal: Blood (2020)
Neoadjuvant Gene-Mediated Cytotoxic Immunotherapy for Non-Small-Cell Lung Cancer: Safety and Immunologic Activity
Authors: Jarrod D. Predina, Andrew R. Haas, Marina Martinez, Shaun O’Brien, Edmund K. Moon, Patrick Woodruff, Jason Stadanlick, Christopher Corbett, Lydia Frenzel-Sulyok, Mitchell G. Bryski, Evgeniy Eruslanov, Charuhas Deshpande, Corey Langer, Laura K. Aguilar, Brian W. Guzik, Andrea G. Manzanera, Estuardo Aguilar-Cordova, Sunil Singhal, Steven M. Albelda
Journal: Molecular Therapy (2020)

Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach involving local delivery of a replication-deficient adenovirus expressing herpes simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation that promotes immunogenic tumor cell death, antigen-presenting cell activation, and T cell stimulation. This phase I dose-escalation pilot trial assessed bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were candidates for surgery. A single intra-tumoral AdV-tk injection in three dose cohorts (maximum 10
Molecular Insights in Transmission of Cancer From an Organ Donor to Four Transplant Recipients
Authors: Chloe E. Atreya, Eric A. Collisson, Meyeon Park, James P. Grenert, Spencer C. Behr, Amalia Gonzalez, Jonathan Chou, Samantha Maisel, Terence W. Friedlander, Chris E. Freise, Jun Shoji, Thomas J. Semrad, Jessica Van Ziffle, Peter Chin-Hong
Journal: Journal of the National Comprehensive Cancer Network (2020)

Organ donors are systematically screened for infection, whereas screening for malignancy is less rigorous. The true incidence of donor-transmitted malignancies is unknown due to a lack of universal tumor testing in the posttransplant setting. Donor-transmitted malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. We describe the detection of a gastrointestinal adenocarcinoma transmitted from a young donor to 4 transplant recipients. Multidimensional histopathologic and genomic profiling showed a CDH1 mutation and MET amplification, consistent with gastric origin. At the time of writing, one patient in this series remains alive and without evidence of cancer after prompt organ explant after cancer was reported in other recipients. Because identification of a donor-derived malignancy changes management, our recommendation is to routinely perform short tandem repeat testing (or a comparable assay) immediately upon diagnosis of cancer in any organ transplant recipient. Routine testing for a donor-origin cancer and centralized reporting of outcomes are necessary to establish a robust evidence base for the future development of clinical practice guidelines.
Single-Cell RNA Sequencing Identifies Expression Patterns Associated with Clinical Responses to Dual-Targeted CAR-T Cell Therapy
Authors: Tyce Kearl, Ao Mei, Ryan Brown, Bryon Johnson, Dina Schneider, Boro Dropulic, Parameswaran Hari, Nirav N. Shah, Subramaniam Malarkannan
Journal: Blood (2020)
Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL/SLL or Richter's Syndrome
Authors: Jennifer L. Crombie, Svitlana Tyekucheva, Zixu Wang, Alexandra Savell, Lisa Brennan, Jessica Lowney, Karen Francoeur, Josie Montegaard, Austin I. Kim, Jacob D. Soumerai, Jon E. Arnason, Allan Louie Cruz, Sigrid Berg, David C. Fisher, Jennifer R Brown, Matthew S. Davids
Journal: Blood (2020)
Hepatokines and adipokines in NASH-related hepatocellular carcinoma
Authors: Ozlem Kucukoglu, Jan-Peter Sowa, Guillermo Daniel Mazzolini, Wing-Kin Syn, Ali Canbay
Journal: Journal of Hepatology (2020)

The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD-related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, preventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipokines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors – in particular, angiopoietin-like proteins, fibroblast growth factors, and apelin – for detection or even as therapeutic targets in NAFLD-related HCC.
Pleural empyema secondary to xanthogranulomatous pyelonephritis
Authors: Adam Maxwell, Alison Kent, Marianne Tinkler, Sunil Mathur, Andy Beale
Journal: Thorax (2020)

<h3>Background</h3> Circulating biomarkers for lung damage are lacking. Lung epithelium-specific DNA methylation patterns can potentially report the presence of lung-derived cell-free DNA (cfDNA) in blood, as an indication of lung cell death. <h3>Methods</h3> We sorted human lung alveolar and bronchial epithelial cells from surgical specimens, and obtained their methylomes using whole-genome bisulfite sequencing. We developed a PCR-sequencing assay determining the methylation status of 17 loci with lung-specific methylation patterns, and used it to assess lung-derived cfDNA in the plasma of healthy volunteers and patients with lung disease. <h3>Results</h3> Loci that are uniquely unmethylated in alveolar or bronchial epithelial cells are enriched for enhancers controlling lung-specific genes. Methylation markers extracted from these methylomes revealed that normal lung cell turnover likely releases cfDNA into the air spaces, rather than to blood. People with advanced lung cancer show a massive elevation of lung cfDNA concentration in blood. Among individuals undergoing bronchoscopy, lung-derived cfDNA is observed in the plasma of those later diagnosed with lung cancer, and to a lesser extent in those diagnosed with other lung diseases. Lung cfDNA is also elevated in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) compared with patients with stable disease, and is associated with future exacerbation and mortality in these patients. <h3>Conclusions</h3> Universal cfDNA methylation markers of normal lung epithelium allow for mutation-independent, sensitive and specific detection of lung-derived cfDNA, reporting on ongoing lung injury. Such markers can find broad utility in the study of normal and pathologic human lung dynamics.
Abstract 491: E-cigarette Aerosol Elevates Cardiovascular Oxidative Stress in Mice With Aldehyde Dehydrogenase 2 Deficiency
Authors: Xuan Yu, Xiaocong Zeng, Ri Chen, Pritam Sinharoy, Eric R Gross
Journal: Circulation Research (2020)

Introduction: E-cigarette aerosol contains reactive aldehydes including acetaldehyde, formaldehyde, and acrolein when e-cigarette is heated. Approximately 560 million people worldwide cannot efficiently metabolize aldehydes present in e-cigarette aerosol, due to a genetic deficiency in aldehyde dehydrogenase 2 enzyme (ALDH2), known as ALDH2*2. Little is known how aldehyde exposure from e-cigarettes, coupled with genetic differences in aldehyde metabolism, affects cardiovascular oxidative stress both at a physiological and cellular level. Hypothesis: E-cigarette aerosol exposure will elevate heart rate and cellular oxidative stress more substantially in ALDH2*2 knock-in mice versus wild type ALDH2 mice. Methods: To measure aldehyde levels, e-cigarette Juul aerosols were collected and quantified by selective ion flow gas mass spectrometry. Further, age-matched male wild type and homozygous ALDH2*2 mice (8-10 weeks old, ~25g) were implanted with EKG telemeters. After surgical recovery, mice were paired by genotype (one wild type ALDH2 and one ALDH2*2 mice) and exposed to either Juul aerosol or room air 4 sessions per day for 10 days. For each session, 7 puffs/min were drawn for the first two minutes (a total of 14 puffs), and the whole body exposure to Juul aerosol lasted 7 minutes, continued with 23 minutes smoking-free intervals in each session. Mice EKG waveforms were recorded daily. After 10 days of exposure, heart homogenates were subjected to biochemical assays including lipid peroxidation, 4-HNE protein adduct formation, and protein carbonylation. Results: Quantification of reactive aldehyde levels in e-cigarettes revealed that Juul aerosol contained acetaldehyde (5.3±0.32 ppm), formaldehyde (0.20±0.02 ppm), and acrolein (0.09±0.01 ppm). When exposed to Juul aerosol, ALDH2*2 mice showed a maximal increase in heart rate unlike ALDH2 wild type mice (774.6±29.5 bpm versus 678.9±32.8 bpm respectively, * p &lt;0.01, n=8) at day 6. Furthermore, heart homogenates from ALDH2*2 mice demonstrated exacerbated oxidative stress, including higher level of 4-HNE adducts (1.5-fold), protein carbonyls (1.5-fold) and lipid peroxides (2-fold) relative to hearts from wild type ALDH2 mice, when both genotype mice were exposed to Juul e-cigarette aerosol (n=4/group). Conclusions: These findings indicate e-cigarette aerosols contain reactive aldehydes, primarily acetaldehyde. A deficiency in reactive aldehyde metabolism by having an ALDH2*2 deficiency may contribute to increases in heart rate and oxidative stress within the cardiovascular system while smoking e-cigarettes.
Anger and confrontation during the COVID-19 pandemic: a national cross-sectional survey in the UK
Authors: Louise E Smith, Bobby Duffy, Vivienne Moxham-Hall, Lucy Strang, Simon Wessely, G James Rubin
Journal: Journal of the Royal Society of Medicine (2020)

Objectives To investigate factors associated with anger or confronting others due to COVID-19. Design Online cross-sectional survey. Setting Data were collected between 17 and 20 July 2020. Participants A total of 2237 participants living in the UK aged 16–75 years. Main outcome measures Reporting having had arguments, felt angry or fallen out with others because of COVID-19. Reporting having confronted or reported someone to the authorities, or that you had been confronted or reported to the authorities, for not wearing a face covering; not keeping your distance from others or being in too large a group; or alternatively following recommended measures too carefully. We used logistic regression analyses to identify factors associated with anger and confrontation. Results Most participants reported having had arguments, feeling angry or fallen out with others because of COVID-19 (56%, n = 1255). Twenty-two percent (n = 500) of participants reported that they had confronted or reported someone. Fourteen percent (n = 304) of participants reported that they had been confronted or reported by someone. Confronting someone, having been confronted and feeling angry or having had arguments were strongly associated with each other. Anger and confrontation were associated with younger age, greater likelihood of experiencing significant financial difficulties due to the pandemic, greater perceived risk of COVID-19 and getting information about COVID-19 from social media. Conclusions Measures put in place to prevent the spread of COVID-19 have caused considerable strain. Increased support, clear messaging on the rationale for easing restrictions and combatting misinformation on social media may all help decrease tension.
Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts
Authors: Hugo A Penny, Suneil A Raju, Michelle S Lau, Lauren JS Marks, Elisabeth MR Baggus, Julio C Bai, Gabrio Bassotti, Hetty J Bontkes, Antonio Carroccio, Mihai Danciu, Mohammad H Derakhshan, Arzu Ensari, Azita Ganji, Peter H R Green, Matt W Johnson, Sauid Ishaq, Benjamin Lebwohl, Adam Levene, Roxana Maxim, Hamid Mohaghegh Shalmani, Mohammad Rostami-Nejad, David Rowlands, Irene A Spiridon, Amitabh Srivastava, Umberto Volta, Vincenzo Villanacci, Graeme Wild, Simon S Cross, Kamran Rostami, David S Sanders
Journal: Gut (2020)

Objective We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients. Design The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD. Results Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively. Conclusion Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.
The Rationale, Design, and Baseline Characteristics of a Phase 2 Study to Evaluate the Safety and Efficacy of Ropeginterferon Alfa-2b (P1101) in Japanese Patients with Polycythemia Vera for Whom the Current Standard of Care Is Difficult to Apply
Authors: Keita Kirito, Kazuya Shimoda, Katsuto Takenaka, Albert Qin, Oleh Zagrijtschuk, Toshiaki Sato, Narihisa Miyachi, Hiroaki Kawase, Katsuya Yonezu, Norio Komatsu
Journal: Blood (2020)
Safety and Efficacy of CD19-CAR T Cells in Richter's Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia
Authors: Ohad Benjamini, Avichai Shimoni, Michal Besser, Noga Shem-Tov, Ivetta Danylesko, Ronit Yerushalmi, Drorit Grizim Merkel, Tamar Tadmor, David Lavie, Riva Fineman, Elad Jacobi, Arnon Nagler, Abraham Avigdor
Journal: Blood (2020)
Validation of a Modified Anti-FXa Assay on STA-Compact Analyzer for Measuring FXa Inhibitor Levels in the Presence of Andexanet Alfa
Authors: Juan Cardenas, Jayaprakash Kotha, Genmin Lu, Pamela B. Conley, Matthieu Bourdin, Tristan Herve, Lisa K. Jennings
Journal: Blood (2020)
TAK-573, an Anti-CD38/Attenuated Ifnα Fusion Protein, Has Clinical Activity and Modulates the Ifnα Receptor (IFNAR) Pathway in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Dan T. Vogl, Jonathan L. Kaufman, Sara A. Holstein, Omar Nadeem, Elizabeth O'Donnell, Kaveri Suryanarayan, Sabrina Collins, Xavier Parot, Maria Chaudhry
Journal: Blood (2020)
Retrospective analysis on confirmation rates for referred positive rotavirus samples in England, 2016 to 2017: implications for diagnosis and surveillance
Authors: Cristina C Celma, Stuart Beard, Amy Douglas, Shan Wong, Nana-Kwame Osafo, Matthew Hannah, Ashleigh Hale, Gabrielle Huggins, Shamez Ladhani, Jake Dunning
Journal: Eurosurveillance (2020)

BackgroundRapid diagnostic tests are commonly used by hospital laboratories in England to detect rotavirus (RV), and results are used to inform clinical management and support national surveillance of the infant rotavirus immunisation programme since 2013. In 2017, the Public Health England (PHE) national reference laboratory for enteric viruses observed that the presence of RV could not be confirmed by PCR in a proportion of RV-positive samples referred for confirmatory detection.AimWe aimed to compare the positivity rate of detection methods used by hospital laboratories with the PHE confirmatory test rate.MethodsRotavirus specimens testing positive at local hospital laboratories were re-tested at the PHE national reference laboratory using a PCR test. Confirmatory results were compared to original results from the PHE laboratory information management system.ResultsHospital laboratories screened 70.1% (2,608/3,721) of RV samples using immunochromatographic assay (IC) or rapid tests, 15.5% (578/3,721) using enzyme immunoassays (EIA) and 14.4% (535/3,721) using PCR. Overall, 1,011/3,721 (27.2%) locally RV-positive samples referred to PHE in 2016 and 2017 failed RV detection using the PHE reference laboratory PCR test. Confirmation rates were 66.9% (1,746/2,608) for the IC tests, 87.4% (505/578) for the EIA and 86.4% (465/535) for the PCR assays. Seasonal confirmation rate discrepancies were also evident for IC tests.ConclusionsThis report highlights high false positive rates with the most commonly used RV screening tests and emphasises the importance of implementing verified confirmatory tests for RV detections. This has implications for clinical diagnosis and national surveillance.
Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers
Authors: Erica S. Tsang, Cameron J. Grisdale, Erin Pleasance, James T. Topham, Karen Mungall, Caralyn Reisle, Caleb Choo, Marcus Carreira, Reanne Bowlby, Joanna M. Karasinska, Daniel MacMillan, Laura M. Williamson, Eric Chuah, Richard A. Moore, Andrew J. Mungall, Yongjun Zhao, Basile Tessier-Cloutier, Tony Ng, Sophie Sun, Howard J. Lim, David F. Schaeffer, Daniel J. Renouf, Stephen Yip, Janessa Laskin, Marco A. Marra, Steven J.M. Jones, Jonathan M. Loree
Journal: Clinical Cancer Research (2020)

Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were EML4-ALK in thoracic malignancies (9/69, 13%), and CMTM8-CMTM7 in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as NTRK2 (novel partners: SHC3, DAPK1), and NTRK3 (novel partners: POLG, PIBF1).Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
Improvements in Health-Related Quality of Life for Patients Treated with LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy
Authors: Julie Kanter, John F. Tisdale, Markus Y Mapara, Janet L. Kwiatkowski, Lakshmanan Krishnamurti, Ren Chen, Meghan E. Gallagher, Yuchen Ding, Sunita Goyal, Clark Paramore, Alexis A. Thompson, Mark C. Walters
Journal: Blood (2020)
Towards a carbon neutral NHS: plant based catering, carbon footprint of all procedures, and embedding the commitment
Authors: Jeremy Wight
Journal: BMJ (2020)

NHS England’s report Delivering a “Net Zero” National Health Service 12 leaves out three important considerations. It states that food and catering account for 6% of total emissions but makes no reference to the vastly greater emissions generated by meat (particularly beef and lamb) and dairy products compared with plant based diets. Adopting plant based catering for the whole of the NHS would be straightforward to implement …
Impact of Oral Arginine Therapy on Global Arginine Bioavailability in Nigerian Children with Sickle Cell Anemia and Vaso-Occlusive Pain
Authors: Richard Onalo, Peter Cooper, Barend C. Vorster, Marli Dercksen, Antoinette Cilliers, Uche Nnebe-Agumadu, Claudia R. Morris
Journal: Blood (2020)