tbuckley/cabot-search huggingface dataset:
Physiologic Target, Molecular Evolution, and Pathogenic Functions of a Monoclonal Anti–Citrullinated Protein Antibody Obtained From a Patient With Rheumatoid Arthritis
Authors: Tatsuhiko Ozawa, Kazuhisa Ouhara, Reina Tsuda, Syuichi Munenaga, Hidemi Kurihara, Hiroki Kohno, Hiroshi Hamana, Eiji Kobayashi, Hirofumi Taki, Kazuyuki Tobe, Eiji Sugiyama, Atsushi Muraguchi, Hiroyuki Kishi
Journal: Arthritis & Rheumatology (2020)

In plasma from a patient with rheumatoid arthritis (RA), we previously isolated a human monoclonal anti-citrullinated protein antibody (ACPA), CCP-Ab1, that recognizes various citrullinated antigens. In this study, we aimed to explore the physiologic target of CCP-Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA.The target protein of CCP-Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline-reverted (GL-rev) CCP-Ab1 was generated, and its reactivity was compared to that of mature CCP-Ab1. The functions of CCP-Ab1 and GL-rev CCP-Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis-prone SKG mice.CCP-Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL-rev CCP-Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (P < 0.05). The elements implicated in GL-rev CCP-Ab1 binding to a citrullinated peptide, cfc1-cyc, were almost identical to those implicated in CCP-Ab1 binding. In arthritis-prone SKG mice, CCP-Ab1, but not GL-rev CCP-Ab1, induced significant exacerbation of experimental arthritis (P < 0.05). Increased production of interleukin-6, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP-Ab1 compared to those treated with GL-rev CCP-Ab1 (P < 0.05). Furthermore, the immune complex formed by CCP-Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP-Ab1 (P < 0.05 versus control treatment groups).These data show that germline-encoded CCP-Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA.
Respiratory failure and non-invasive respiratory support during the covid-19 pandemic: an update for re-deployed hospital doctors and primary care physicians
Authors: Thomas W Nicholson, Nick P Talbot, Annabel Nickol, Andrew J Chadwick, Oliver Lawton
Journal: BMJ (2020)

What you need to know• Most patients who become seriously unwell with covid-19 do so primarily due to acute type 1 respiratory failure and benefit from early recognition of respiratory deterioration and appropriate escalation in respiratory support • Respiratory deterioration can be identified by an increasing respiratory rate, an inability to talk in full sentences, the use of accessory muscles of breathing, decreasing oxygen levels in the blood, and an increased requirement for supplementary oxygen • All patients with covid-19 admitted to hospital and many of those in the community should have a ceiling of care established at the earliest opportunityIn response to the covid-19 pandemic, many health systems attempted to rapidly reorganise their healthcare workforce in the first half of 2020, including redeployment of doctors from primary care and non-frontline specialties to acute care wards. 1 Preparedness for potential future redeployment remains essential given the risk of further waves of covid-19 as society negotiates repeated cycles of lockdown and reopening.Most people who become seriously unwell with covid-19 have an acute respiratory illness, 2 -4 and about 14% will require non-invasive respiratory support. 2 In addition to shifting into acute care settings in the short term, primary care clinicians will also be caring for patients (or their loved ones) recovering from potentially traumatic experiences of respiratory illness.This article updates primary care and non-respiratory or intensivist specialist doctors on the recognition and non-invasive management of acute respiratory failure and will aid general practitioners in the subsequent outpatient support of patients during their recovery. Case scenarioA 50 year old man has been self isolating for eight days with fever and a cough.He was brought to the emergency department by ambulance after becoming increasingly breathless over the past two days.He can speak complete sentences but has an elevated respiratory rate of 24 breaths per minute (normal range 12-20).His peripheral oxygen saturation (SpO2) was 72% breathing room air when the paramedics arrived, and 90% on oxygen therapy (4 L/min) via nasal cannula.Cardiovascular observations are normal and he is apyrexial.
Snapshot PCR surveillance for SARS-CoV-2 in hospital staff in England
Authors: Colin S Brown, Kathryn Clare, Meera Chand, Julie Andrews, Cressida Auckland, Sarah Beshir, Saher Choudhry, Kerrie Davies, Jane Freeman, Andrew Gallini, Rachel Moores, Trupti Patel, Gosia Poznalska, Alison Rodger, Stella Roberts, Christopher Rooney, Mark Wilcox, Simon Warren, Joanna Ellis, Robin Gopal, Jake Dunning, Maria Zambon, Susan Hopkins
Journal: Journal of Infection (2020)
COVID-19 phenotypes: leading or misleading?
Authors: Luciano Gattinoni, Luigi Camporota, John J. Marini
Journal: European Respiratory Journal (2020)

<b>Comment on the editorial by Bos <i>et al.</i> about</b><b>"perils of premature phenotyping in COVID-19", querying the risks of COVID-19 phenotypes and how the arguments put forward can further the cause of patients and clinicians</b>https://bit.ly/2Y6VZz9
Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study
Authors: George Goshua, Alexander B Pine, Matthew L Meizlish, C-Hong Chang, Hanming Zhang, Parveen Bahel, Audrey Baluha, Noffar Bar, Robert D Bona, Adrienne J Burns, Charles S Dela Cruz, Anne Dumont, Stephanie Halene, John Hwa, Jonathan Koff, Hope Menninger, Natalia Neparidze, Christina Price, Jonathan M Siner, Christopher Tormey, Henry M Rinder, Hyung J Chun, Alfred I Lee
Journal: The Lancet Haematology (2020)
Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade
Authors: Keith Rennier, Woo Jae Shin, Ethan Krug, Gurpal Virdi, Russell K. Pachynski
Journal: Clinical Cancer Research (2020)

Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, ChemR23. RARRES2 is widely expressed in nonhematopoietic tissues and often downregulated across multiple tumor types compared with normal tissue. Recent studies show that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, in part, by immune effector cells recruitment. However, as tumor cells express functional chemokine/chemoattractant receptors that impact their phenotype, we hypothesized that chemerin may have additional, tumor-intrinsic effects.We investigated the effect of exogenous chemerin on human prostate and sarcoma tumor lines. Key signaling pathway components were elucidated using qPCR, Western blotting, siRNA knockdown, and specific inhibitors. Functional consequences of chemerin treatment were evaluated using in vitro and in vivo studies.We show for the first time that human tumors exposed to exogenous chemerin significantly upregulate PTEN expression/activity, and concomitantly suppress programmed death ligand-1 (PD-L1) expression. CMKLR1 knockdown abrogated chemerin-induced PTEN and PD-L1 modulation, exposing a novel CMKLR1/PTEN/PD-L1 signaling cascade. Targeted inhibitors suggested signaling was occurring through the PI3K/AKT/mTOR pathway. Chemerin treatment significantly reduced tumor migration, while significantly increasing T-cell-mediated cytotoxicity. Chemerin treatment was as effective as both PD-L1 knockdown and the anti-PD-L1 antibody, atezolizumab, in augmenting T-cell-mediated tumor lysis. Forced expression of chemerin in human DU145 tumors significantly suppressed in vivo tumor growth, and significantly increased PTEN and decreased PD-L1 expression.Collectively, our data show a novel link between chemerin, PTEN, and PD-L1 in human tumor lines, which may have a role in improving T-cell-mediated immunotherapies.
Abstract 12214: ODYSSEY EAST - A Randomized, Double-blind, Parallel Group Study to Evaluate Alirocumab Efficacy and Safety Versus Ezetimibe In High-Risk Patients With Hypercholesterolemia on Maximally Tolerated Statin in China, India, and Thailand
Authors: Yaling Han, Jiyan Chen, Vijaykumar Chopra, Shuyang Zhang, Guohai Su, Chang-Sheng Ma, Zhouqing Huang, Yingyan Ma, Zhuhua Yao, Zuyi Yuan, Qiang Zhao, Srun Kuanprasert, Marie T Baccara-Dinet, Garen Manvelian, Jianyong Li, Rui Chen
Journal: Circulation (2019)

Introduction: The PCSK9 inhibitor alirocumab (ALI) has been shown to provide significant low-density lipoprotein cholesterol (LDL-C) reductions. This study was conducted to assess ALI efficacy and ...
Letter regarding article “Stereotactic radiosurgery for non-functioning pituitary adenomas: meta-analysis and International Stereotactic Radiosurgery Society practice opinion”
Authors: Weilin Xu, Xin Hu, Jianmin Zhang
Journal: Neuro-Oncology (2020)

radiosurgery for non-functioning pituitary adenomas: meta-analysis and International Stereotactic Radiosurgery Society practice opinion"We read with great interest the meta-analysis by Kotecha et al, 1 which evaluated the efficacy and toxicities following stereotactic radiosurgery (SRS) for nonfunctioning pituitary adenomas (NFAs).Finally, the authors suggested that SRS is an effective and safe treatment for patients with NFAs.However, some issues should be discussed.First, although the authors declared that they have avoided double counting the cases in different studies, some of the included studies still shared the same series of patients.The studies by Lee et al 2 (1988-2012), Sheehan et al 3 (1988-2011), Cohen Inbar et al 4 (1997-2015), and Park et al 5 (1987-2009) all included patients from University of Pittsburgh (duplication 1).In addition, the studies by Wowra et al 6 (1993-2002) and Muacevic et al 7 (1994-2004) both included patients from German Gamma Knife Center Munich of Ludwig-Maximilians University (duplication 2).These studies shared a certain period in the same department.Therefore, the data of these studies should not be pooled because of the duplicate data, which would inevitably increase the bias of final results.Considering the number of patients and following period, the studies with the latest report of the largest number of patients should be included.Therefore, the study by Sheehan et al (1988Sheehan et al ( -2011) ) should be included for duplication 1, and the study by Muacevic et al should be included for duplication 2.Second, after excluding the studies with duplicate data, I pooled the results again.The results of random effects metaanalyses showed that the efficacy of 5-year local control for single fraction SRS was 98.0% (95% CI: 96.0-99.0%),which was higher than that of hypofractionated stereotactic radiotherapy, 97.0% (95% CI: 93.0-98.0%)(Fig. 1).Moreover, the metaanalysis for 10-year local control after SRS with random effects indicated the efficacy is 90% (95% CI: 79.0-97.0%),and the rate of hypopituitarism after SRS is 16.0% (95% CI: 08.0-26.0%),which is much lower than that reported by Kotecha et al.Other results were the same with this meta-analysis.
A Half-Century of Progress in Health — A Perspective Series in Honor of the 50th Anniversary of the National Academy of Medicine
Authors: Victor J. Dzau, Harvey V. Fineberg, Kenneth I. Shine, Samuel O. Thier, Debra Malina, Stephen Morrissey
Journal: New England Journal of Medicine (2020)

50 Years of Progress in Health The Journal announces a new Perspective series to mark the 50th anniversary of the National Academy of Medicine, focusing on progress in health over the half century....
Safety of Tofacitinib in a Real-World Cohort of Patients With Ulcerative Colitis
Authors: Parakkal Deepak, Quazim A. Alayo, Aava Khatiwada, Bixuan Lin, Marc Fenster, Christina Dimopoulos, Geoffrey Bader, Roni Weisshof, Michael Jacobs, Alexandra Gutierrez, Matthew A. Ciorba, George P. Christophi, Anish Patel, Robert P. Hirten, Jean-Frederic Colombel, David T. Rubin, Christina Ha, Poonam Beniwal-Patel, Ryan C. Ungaro, Gaurav Syal, Joel Pekow, Benjamin L. Cohen, Andres Yarur
Journal: Clinical Gastroenterology and Hepatology (2020)
Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the <scp>H</scp>eart <scp>F</scp>ailure <scp>A</scp>ssociation (<scp>HFA</scp>), the <scp>E</scp>uropean <scp>A</scp>ssociation of <scp>C</scp>ardiovascular <scp>I</scp>maging (<scp>EACVI</scp>) and the <scp>Cardio‐Oncology C</scp>ouncil of the <scp>E</scp>uropean <scp>S</scp>ociety of <scp>C</scp>ardiology (<scp>ESC</scp>)
Authors: Jelena Čelutkienė, Radek Pudil, Teresa López‐Fernández, Julia Grapsa, Petros Nihoyannopoulos, Jutta Bergler‐Klein, Alain Cohen‐Solal, Dimitrios Farmakis, Carlo Gabriele Tocchetti, Stephan von Haehling, Vassilis Barberis, Frank A. Flachskampf, Indrė Čeponienė, Eva Haegler‐Laube, Thomas Suter, Tomas Lapinskas, Sanjay Prasad, Rudolf A. de Boer, Kshama Wechalekar, Markus S. Anker, Zaza Iakobishvili, Chiara Bucciarelli‐Ducci, Jeanette Schulz‐Menger, Bernard Cosyns, Oliver Gaemperli, Yury Belenkov, Jean‐Sébastien Hulot, Maurizio Galderisi, Patrizio Lancellotti, Jeroen Bax, Thomas H. Marwick, Ovidiu Chioncel, Tiny Jaarsma, Wilfried Mullens, Massimo Piepoli, Thomas Thum, Stephane Heymans, Christian Mueller, Brenda Moura, Frank Ruschitzka, Jose Luis Zamorano, Giuseppe Rosano, Andrew J.S. Coats, Riccardo Asteggiano, Petar Seferovic, Thor Edvardsen, Alexander R. Lyon
Journal: European Journal of Heart Failure (2020)
Abstract B28: Optimizing DNA processing and ovarian cancer methylation-specific PCR assays for the detection of early-stage ovarian cancer
Authors: Kristina Warton, Nicole Yuwono, Claire Henry, Neville Hacker, Caroline Ford
Journal: Clinical Cancer Research (2020)

Abstract Background: Ovarian cancer screening has the potential to greatly reduce mortality by shifting the time of diagnosis to an early stage when the tumor is confined to a single site and can be completely cured by surgical removal. Ovarian cancer DNA is present in blood and has a distinct methylation profile that distinguishes it from healthy blood cells, thus making it a target for ovarian cancer diagnosis via a blood test. However, while the presence of this DNA in the blood of cancer patients is well established, low abundance and DNA fragmentation present a barrier to developing clinical applications that target it. Methods: We are systematically evaluating and optimizing each step of DNA extraction, processing, and analysis to increase the sensitivity of cancer DNA detection by PCR. At the same time, we are developing PCR assays to detect ovarian cancer specific methylation based on a previous tumor and blood screen that identified 73 methylated candidate biomarker regions. Results: We have found that inhibitors of the PCR reaction introduced into the sample during DNA extraction and bisulphite treatment limit the total amount of DNA that can be analyzed, and thus the sensitivity of the test. Precipitation of the DNA samples prior to PCR analysis removes the inhibitors and increases useable sample volume and thus sensitivity. We have also developed methylation-specific PCR assays for DNA regions that are methylated in ovarian tumor tissue, and unmethylated in white blood cells. Conclusions: We are progressing our candidate methylated DNA ovarian cancer biomarkers closer to testing in clinical samples. Our results on sample processing and DNA analysis methods to enable ovarian cancer DNA detection are relevant to all cancer types for which cell-free tumor DNA has clinical applications. Citation Format: Kristina Warton, Nicole Yuwono, Claire Henry, Neville Hacker, Caroline Ford. Optimizing DNA processing and ovarian cancer methylation-specific PCR assays for the detection of early-stage ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B28.
Biopsy outperforms reflectance confocal microscopy in diagnosing and subtyping basal cell carcinoma: results and experiences from a randomized controlled multicentre trial*
Authors: W. Woliner–van der Weg, M. Peppelman, Y.S. Elshot, M.B. Visch, M.B. Crijns, H.A.C. Alkemade, E.M. Bronkhorst, E. Adang, A. Amir, M.J.P. Gerritsen, P.E.J. Erp, S.F.K. Lubeek
Journal: British Journal of Dermatology (2020)

Reflectance confocal microscopy (RCM) is a noninvasive method for skin assessment, allowing entire lesion evaluation up to the papillary dermis. RCM is a potentially attractive alternative to punch biopsy (PB) in basal cell carcinoma (BCC). To determine the diagnostic accuracy of RCM vs. PB in diagnosing and subtyping BCC, and to study patient satisfaction and preferences. Patients with a clinically suspected primary BCC were randomized between RCM and biopsy. Conventional surgical excision or follow‐up were used as reference. Sensitivity and specificity for BCC diagnosis and subtyping were calculated for both methods. BCC subtype was stratified based on clinical relevance: aggressive (infiltrative/micronodular) vs. nonaggressive (superficial/nodular) histopathological subtype and superficial vs. nonsuperficial BCC. Data on patient satisfaction and preferences were collected using a questionnaire and a contingent valuation method. Sensitivity for BCC diagnosis was high and similar for both methods (RCM 99·0% vs. biopsy 99·0%; P = 1·0). Specificity for BCC diagnosis was lower for RCM (59·1% vs. 100·0%; P < 0·001). Sensitivity for aggressive BCC subtypes was lower for RCM (33·3% vs. 77·3%; P = 0·003). Sensitivity for nonsuperficial BCC was not significantly different (RCM 88·9% vs. biopsy 91·0%; P = 0·724). Patient satisfaction and preferences were good and highly comparable for both methods. Biopsy outperforms RCM in diagnosing and subtyping clinically suspected primary BCC. This outcome does not support routine clinical implementation of RCM, as a replacement for PBs in this patient group.
Dose Calculations and Dose-Effect Relationships in 177Lu-PSMA I&amp;T Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer
Authors: Sandra Barna, Alexander R. Haug, Markus Hartenbach, Sazan Rasul, Bernhard Grubmüller, Gero Kramer, Matthias Blaickner
Journal: Clinical Nuclear Medicine (2020)

Introduction Dose response of 22 patients experiencing mCRPC (metastatic castration-resistant prostate cancer) to 177 Lu-PSMA I&amp;T radionuclide therapy was investigated. Dosimetry calculations are used to assess correlations between dosimetric quantities and biomarker values. Methods The patients’ age range was 74 ± 7 years at the time of the investigated treatment cycle, and the mean injected activity was 7416 ± 218 MBq. Planar images at several time points postinjection were used for evaluation of absorbed doses to organs and lesion. 68 Ga-PSMA PET/CT follow-up imaging enabled the determination of individual tumor molecular volume (TMV) shrinkage. Changes in 7 different biomarkers after the first treatment cycle were correlated with the calculated absorbed organ and TMV doses, resulting in a total number of 259 investigated correlations. Results Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively). Only 37 of 259 possible correlations turned out to be statistically significant, 26 of which are associated with the absorbed dose of an organ and the decrease of alkaline phosphatases. Conclusions Although treatment with 177 Lu-PSMA I&amp;T leads to a big reduction of TMV in patients with mCRPC, the lack of correlations calls for studies using voxel-wise dosimetry based on SPECT/CTs.
Inefficient CAR-proximal signaling blunts antigen sensitivity
Authors: Venugopal Gudipati, Julian Rydzek, Iago Doel-Perez, Vasco Dos Reis Gonçalves, Lydia Scharf, Sebastian Königsberger, Elisabeth Lobner, Renate Kunert, Hermann Einsele, Hannes Stockinger, Michael Hudecek, Johannes B. Huppa
Journal: Nature Immunology (2020)
Reporting Radical Cystectomy Outcomes Following Implementation of Enhanced Recovery After Surgery Protocols: A Systematic Review and Individual Patient Data Meta-analysis
Authors: Stephen B. Williams, Marcus G.K. Cumberbatch, Ashish M. Kamat, Ibrahim Jubber, Preston S. Kerr, John S. McGrath, Hooman Djaladat, Justin W. Collins, Vignesh T. Packiam, Gary D. Steinberg, Eugene Lee, Wassim Kassouf, Peter C. Black, Yannick Cerantola, James W.F. Catto, Siamak Daneshmand
Journal: European Urology (2020)
Efinaconazole 10% topical solution for the treatment of onychomycosis in pediatric patients: Open-label phase 4 study
Authors: Lawrence F. Eichenfield, Boni Elewski, Jeffrey L. Sugarman, Ted Rosen, Tracey C. Vlahovic, Aditya K. Gupta, Radhakrishnan Pillai, Eric Guenin
Journal: Journal of the American Academy of Dermatology (2020)
Covid-19: Airborne transmission is being underestimated, warn experts
Authors: Owen Dyer
Journal: BMJ (2020)

Microscopic respiratory droplets generated by talking and breathing can hover in the air for minutes or hours and drift many metres horizontally before infecting people, argue 239 experts from 32 countries, in a commentary published in Clinical Infectious Diseases. 1 "We appeal to the medical community and to the relevant national and international bodies to recognise the potential for airborne spread of covid-19," wrote the scientists, who include physicians, epidemiologists, and experts in environmental health and building design.