tbuckley/cabot-search huggingface dataset:
Neutrophil and Eosinophil Extracellular Traps in Hodgkin Lymphoma
Authors: Ivo M. B. Francischetti, Julie C. Alejo, Ranjit Sivanandham, Theresa Davies-Hill, Patricia Fetsch, Ivona Pandrea, Elaine S. Jaffe, Stefania Pittaluga
Journal: HemaSphere (2021)

Classic Hodgkin lymphoma (cHL), nodular sclerosis (NS) subtype, is characterized by the presence of Hodgkin/Reed-Sternberg (HRS) cells in an inflammatory background containing neutrophils and/or eosinophils. Both types of granulocytes release extracellular traps (ETs), web-like DNA structures decorated with histones, enzymes, and coagulation factors that promote inflammation, thrombosis, and tumor growth. We investigated whether ETs from neutrophils (NETs) or eosinophils (EETs) are detected in cHL, and evaluated their association with fibrosis. We also studied expression of protease-activated receptor-2 (PAR-2) and phospho-extracellular signal-related kinase (p-ERK), potential targets/effectors of ETs-associated elastase, in HRS cells. Expression of tissue factor (TF) was evaluated, given the procoagulant properties of ETs. We analyzed 32 HL cases, subclassified as 12 NS, 5 mixed-cellularity, 5 lymphocyte-rich, 1 lymphocyte-depleted, 4 nodular lymphocyte-predominant HL (NLPHL), and 5 reactive nodes. Notably, a majority of NS cHL cases exhibited NET formation by immunohistochemistry for citrullinated histones, with 1 case revealing abundant EETs. All other cHL subtypes as well as NLPHL were negative. Immunofluorescence microscopy confirmed NETs with filamentous/delobulated morphology. Moreover, ETs formation correlates with concurrent fibrosis (r = 0.7999; 95% CI, 0.6192-0.9002; P ≤ 0.0001). Results also showed that HRS cells in NS cHL expressed PAR-2 with nuclear p-ERK staining, indicating a neoplastic or inflammatory phenotype. Remarkably, TF was consistently detected in the endothelium of NS cHL cases compared with other subtypes, in keeping with a procoagulant status. A picture emerges whereby the release of ETs and resultant immunothrombosis contribute to the inflammatory tumor microenvironment of NS cHL. This is the first description of NETs in cHL.
Ronapreve for prophylaxis and treatment of covid-19
Authors: David B Sidebottom, Dipender Gill
Journal: BMJ (2021)

On 20 August 2021, Ronapreve received conditional marketing authorisation for the prevention and treatment of covid-19 in the UK. 1 Ronapreve (REGEN-COV in the US) comprises two monoclonal antibodies, casirivimab and imdevimab, that target the SARS-CoV-2 spike protein to reduce the risk and severity of covid-19 in selected patients. 2 -5Although Ronapreve's approval represents a welcome expansion in the armamentarium against covid-19, it also brings difficult questions about who should be eligible for treatment.
Correction: Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role
Authors: Paula Rodríguez-Otero, María Victoria Mateos, Joaquín Martínez-López, Nerea Martín-Calvo, Miguel-Teodoro Hernández, Enrique M. Ocio, Laura Rosiñol, Rafael Martínez, Ana-Isabel Teruel, Norma C. Gutiérrez, Joan Bargay, Enrique Bengoechea, Yolanda González, Jaime Pérez de Oteyza, Mercedes Gironella, Cristina Encinas, Jesús Martín, Carmen Cabrera, Luis Palomera, Felipe de Arriba, María Teresa Cedena, Bruno Paiva, Noemí Puig, Albert Oriol, Joan Bladé, Juan José Lahuerta, Jesús F. San Miguel
Journal: Leukemia (2019)
Synthesis of precision antibody conjugates using proximity-induced chemistry
Authors: Yu J Cao, Chenfei Yu, Kuan-Lin Wu, Xuechun Wang, Dong Liu, Zeru Tian, Lijun Zhao, Xuexiu Qi, Axel Loredo, Anna Chung, Han Xiao
Journal: Theranostics (2021)

Rationale: Therapeutic antibody conjugates allow for the specific delivery of cytotoxic agents or immune cells to tumors, thus enhancing the antitumor activity of these agents and minimizing adverse systemic effects. Most current antibody conjugates are prepared by nonspecific modification of antibody cysteine or lysine residues, inevitably resulting in the generation of heterogeneous conjugates with limited therapeutic efficacies. Traditional strategies to prepare homogeneous antibody conjugates require antibody engineering or chemical/enzymatic treatments, processes that often affect antibody folding and stability, as well as yield and cost. Developing a simple and cost-effective way to precisely couple functional payloads to native antibodies is of great importance. Methods: We describe a simple proximity-induced antibody conjugation method (pClick) that enables the synthesis of homogeneous antibody conjugates from native antibodies without requiring additional antibody engineering or post-synthesis treatments. A proximity-activated crosslinker is introduced into a chemically synthesized affinity peptide modified with a bioorthogonal handle. Upon binding to a specific antibody site, the affinity peptide covalently attaches to the antibody via spontaneous crosslinking, yielding an antibody molecule ready for bioorthogonal conjugation with payloads. Results: We have prepared well-defined antibody-drug conjugates and bispecific small molecule-antibody conjugates using pClick technology. The resulting conjugates exhibit excellent in vitro cytotoxic activity against cancer cells and, in the case of bispecific conjugates, superb antitumor activity in mouse xenograft models. Conclusions: Our pClick technology enables efficient, simple, and site-specific conjugation of various moieties to the existing native antibodies. This technology does not require antibody engineering or additional UV/chemical/enzymatic treatments, therefore providing a general, convenient strategy for developing novel antibody conjugates.
Financial Profit in Medicine: A Position Paper From the American College of Physicians
Authors: Ryan Crowley, Omar Atiq, David Hilden
Journal: Annals of Internal Medicine (2021)

The steady growth of corporate interest and influence in the health care sector over the past few decades has created a more business-oriented health care system in the United States, helping to spur for-profit and private equity investment. Proponents say that this trend makes the health care system more efficient, encourages innovation, and provides financial stability to ensure access and improve care. Critics counter that such moves favor profit over care and erode the patient-physician relationship. American College of Physicians (ACP) underscores that physicians are permitted to earn a reasonable income as long as they are fulfilling their fiduciary responsibility to provide high-quality, appropriate care within the guardrails of medical professionalism and ethics. In this position paper, ACP considers the effect of mergers, integration, private equity investment, nonprofit hospital requirements, and conversions from nonprofit to for-profit status on patients, physicians, and the health care system.
Activating AhR alleviates cognitive deficits of Alzheimer's disease model mice by upregulating endogenous Aβ catabolic enzyme Neprilysin
Authors: Cheng Qian, Chunjie Yang, Mengting Lu, Jiaxin Bao, Haiyan Shen, Bingquan Deng, Shensen Li, Wenwen Li, Mu Zhang, Changchun Cao
Journal: Theranostics (2021)

Rationale: Neprilysin (NEP) is a major endogenous catabolic enzyme of amyloid β (Aβ). Previous studies have suggested that increasing NEP expression in animal models of Alzheimer's disease had an ameliorative effect. However, the underlying signaling pathway that regulates NEP expression remains unclear. The aryl hydrocarbon receptor (AhR) is a ligand-activated cytoplasmic receptor and transcription factor. Recent studies have shown that AhR plays essential roles in the central nervous system (CNS), but its physiological and pathological roles in regulating NEP are not entirely known. Methods: Western blotting, immunofluorescence, quantitative RT-PCR and enzyme activity assay were used to verify the effects of AhR agonists on NEP in a cell model (N2a) and a mouse model (APP/PS1). Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to investigate the roles of AhR in regulating NEP transcription. Object recognition test and the Morris water maze task were performed to assess the cognitive capacity of the mice. Results: Activating AhR by the endogenous ligand L-Kynurenine (L-KN) or FICZ, or by the exogenous ligand diosmin or indole-3-carbinol (I3C) significantly increases NEP expression and enzyme activity in N2a cells and APP/PS1 mice. We also found that AhR is a direct transcription factor of NEP. Diosmin treatment effectively ameliorated the cognitive disorder and memory deficit of APP/PS1 transgenic mice. By knocking down AhR or using a small molecular inhibitor targeting AhR or NEP, we found that diosmin enhanced Aβ degradation through activated AhR and increased NEP expression. Conclusions: These results indicate a novel pathway for regulating NEP expression in neurons and that AhR may be a potential therapeutic target for the treatment of Alzheimer's disease.
Covid-19: UK will offer third vaccine dose to severely immunosuppressed people
Authors: Jacqui Wise
Journal: BMJ (2021)

Covid-19: UK will offer third vaccine dose to severely immunosuppressed people Jacqui WiseThe UK's Joint Committee on Vaccination and Immunisation (JCVI) has recommended that people with severely weakened immune systems should have a third vaccine dose as part of their primary vaccination schedule against covid-19.The third dose of either the Moderna or the Pfizer-BioNTech vaccine should be offered to people over age 12 who were severely immunosuppressed at the time of their first or second dose, including those with leukaemia, advanced HIV, or recent organ transplants.For 12-17 year olds the Pfizer-BioNTech vaccine is preferred.The JCVI is still deciding on the benefits of booster doses for the rest of the population and is awaiting further evidence to inform this decision.The committee has based its new advice on preliminary data from the Octave trial, which showed that almost everyone who was immunosuppressed did mount an immune response after two doses, as indicated by either antibodies or T cells-but in around 40% of people the levels of antibodies were low.It is not yet clear how much this may affect their protection against covid-19.The JCVI has said that studies are ongoing to see how effective a third dose is in immunosuppressed people, but it is very unlikely to cause significant harms or disadvantages and may offer some benefit.
A novel endoscopic suturing device after endoscopic full-thickness resection of gastric submucosal tumor
Authors: Hideyuki Chiba, Ken Ohata, Hirohito Mori, Hiroki Kuwabara, Yoshinori Sato, Yosuke Tsuji, Fumio Itoh
Journal: Endoscopy (2021)

Endoscopic full-thickness resection (EFTR) is a minimally invasive technique that has shown promising efficacy in the resection of gastrointestinal submucosal tumors. The key to a successful EFTR procedure is the complete closure of the wall defect to prevent peritonitis and the need for surgical intervention [1] [2]. Here, we present a suturing technique to close a gastric wall defect after performing EFTR with Zeosuture M (Zeon Medical Co., Tokyo, Japan), a novel endoscopic suturing device ([Fig. 1]).
Evaluation of some aspects in supervised cell type identification for single-cell RNA-seq: classifier, feature selection, and reference construction
Authors: Wenjing Ma, Kenong Su, Hao Wu
Journal: Genome biology (2021)

Abstract Background Cell type identification is one of the most important questions in single-cell RNA sequencing (scRNA-seq) data analysis. With the accumulation of public scRNA-seq data, supervised cell type identification methods have gained increasing popularity due to better accuracy, robustness, and computational performance. Despite all the advantages, the performance of the supervised methods relies heavily on several key factors: feature selection, prediction method, and, most importantly, choice of the reference dataset. Results In this work, we perform extensive real data analyses to systematically evaluate these strategies in supervised cell identification. We first benchmark nine classifiers along with six feature selection strategies and investigate the impact of reference data size and number of cell types in cell type prediction. Next, we focus on how discrepancies between reference and target datasets and how data preprocessing such as imputation and batch effect correction affect prediction performance. We also investigate the strategies of pooling and purifying reference data. Conclusions Based on our analysis results, we provide guidelines for using supervised cell typing methods. We suggest combining all individuals from available datasets to construct the reference dataset and use multi-layer perceptron (MLP) as the classifier, along with F -test as the feature selection method. All the code used for our analysis is available on GitHub ( https://github.com/marvinquiet/RefConstruction_supervisedCelltyping ).
Role of Venous Endothelial Cells in Developmental and Pathologic Angiogenesis
Authors: Heon-Woo Lee, Yanying Xu, Liqun He, Woosoung Choi, David Gonzalez, Suk-Won Jin, Michael Simons
Journal: Circulation (2021)

Background: Angiogenesis is a dynamic process that involves expansion of a preexisting vascular network that can occur in a number of physiological and pathological settings. Despite its importance, the origin of the new angiogenic vasculature is poorly defined. In particular, the primary subtype of endothelial cells (capillary, venous, arterial) driving this process remains undefined. Methods: Endothelial cells were fate-mapped with the use of genetic markers specific to arterial and capillary cells. In addition, we identified a novel venous endothelial marker gene ( Gm5127 ) and used it to generate inducible venous endothelium-specific Cre and Dre driver mouse lines. Contributions of these various types of endothelial cells to angiogenesis were examined during normal postnatal development and in disease-specific setting. Results: Using a comprehensive set of endothelial subtype-specific inducible reporter mice, including tip, arterial, and venous endothelial reporter lines, we showed that venous endothelial cells are the primary endothelial subtype responsible for the expansion of an angiogenic vascular network. During physiological angiogenesis, venous endothelial cells proliferate, migrating against the blood flow and differentiating into tip, capillary, and arterial endothelial cells of the new vasculature. Using intravital 2-photon imaging, we observed venous endothelial cells migrating against the blood flow to form new blood vessels. Venous endothelial cell migration also plays a key role in pathological angiogenesis. This was observed both in formation of arteriovenous malformations in mice with inducible endothelium-specific Smad4 deletion mice and in pathological vessel growth seen in oxygen-induced retinopathy. Conclusions: Our studies establish that venous endothelial cells are the primary endothelial subtype responsible for normal expansion of vascular networks, formation of arteriovenous malformations, and pathological angiogenesis. These observations highlight the central role of the venous endothelium in normal development and disease pathogenesis.
Clinical Observation on 98 Cases of Hematological Malignancies Treated with Autologous Hematopoietic Stem Cell Transplantation Cryopreserved By Ladder-Style Freezing from Low Temperature Refrigerator to Liquid Nitrogen
Authors: Hu Peng, Tonghua Yang, Renbin Zhao, Keqian Shi, Xun Lai, Yanmei Yang
Journal: Blood (2017)
Altering product placement to create a healthier layout in supermarkets: Outcomes on store sales, customer purchasing, and diet in a prospective matched controlled cluster study
Authors: Christina Vogel, Sarah Crozier, Daniel Penn-Newman, Kylie Ball, Graham Moon, Joanne Lord, Cyrus Cooper, Janis Baird
Journal: PLoS Medicine (2021)

Background Previous product placement trials in supermarkets are limited in scope and outcome data collected. This study assessed the effects on store-level sales, household-level purchasing, and dietary behaviours of a healthier supermarket layout. Methods and findings This is a prospective matched controlled cluster trial with 2 intervention components: (i) new fresh fruit and vegetable sections near store entrances (replacing smaller displays at the back) and frozen vegetables repositioned to the entrance aisle, plus (ii) the removal of confectionery from checkouts and aisle ends opposite. In this pilot study, the intervention was implemented for 6 months in 3 discount supermarkets in England. Three control stores were matched on store sales and customer profiles and neighbourhood deprivation. Women customers aged 18 to 45 years, with loyalty cards, were assigned to the intervention ( n = 62) or control group ( n = 88) of their primary store. The trial registration number is NCT03518151. Interrupted time series analysis showed that increases in store-level sales of fruits and vegetables were greater in intervention stores than predicted at 3 (1.71 standard deviations (SDs) (95% CI 0.45, 2.96), P = 0.01) and 6 months follow-up (2.42 SDs (0.22, 4.62), P = 0.03), equivalent to approximately 6,170 and approximately 9,820 extra portions per store, per week, respectively. The proportion of purchasing fruits and vegetables per week rose among intervention participants at 3 and 6 months compared to control participants (0.2% versus −3.0%, P = 0.22; 1.7% versus −3.5%, P = 0.05, respectively). Store sales of confectionery were lower in intervention stores than predicted at 3 (−1.05 SDs (−1.98, −0.12), P = 0.03) and 6 months (−1.37 SDs (−2.95, 0.22), P = 0.09), equivalent to approximately 1,359 and approximately 1,575 fewer portions per store, per week, respectively; no differences were observed for confectionery purchasing. Changes in dietary variables were predominantly in the expected direction for health benefit. Intervention implementation was not within control of the research team, and stores could not be randomised. It is a pilot study, and, therefore, not powered to detect an effect. Conclusions Healthier supermarket layouts can improve the nutrition profile of store sales and likely improve household purchasing and dietary quality. Placing fruits and vegetables near store entrances should be considered alongside policies to limit prominent placement of unhealthy foods. Trial registration ClinicalTrials.gov NCT03518151 (pre-results)
Assessing COVID-19 Prevention Strategies to Permit the Safe Opening of Residential Colleges in Fall 2021
Authors: A. David Paltiel, Jason L. Schwartz
Journal: Annals of Internal Medicine (2021)

Effective vaccines, improved testing technologies, and decreases in COVID-19 incidence prompt an examination of the choices available to residential college administrators seeking to safely resume in-person campus activities in fall 2021.
Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs and Disease Flare in Patients With Rheumatoid Arthritis—Reply
Authors: Siri Lillegraven, Nina Paulshus Sundlisæter, Espen A. Haavardsholm
Journal: JAMA (2021)

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Circadian rhythms in ischaemic heart disease: key aspects for preclinical and translational research: position paper of the ESC working group on cellular biology of the heart
Authors: Sandrine Lecour, Bastiaan C Du Pré, Hans Erik Bøtker, Bianca J J M Brundel, Andreas Daiber, Sean M Davidson, Peter Ferdinandy, Henrique Girao, Can Gollmann-Tepeköylü, Mariann Gyöngyösi, Derek J Hausenloy, Rosalinda Madonna, Michael Marber, Cinzia Perrino, Maurizio Pesce, Rainer Schulz, Joost P G Sluijter, Sabine Steffens, Sophie Van Linthout, Martin E Young, Linda W Van Laake
Journal: Cardiovascular Research (2021)

Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes.
AAV integration in human hepatocytes
Authors: Dhwanil A. Dalwadi, Andrea Calabria, Amita Tiyaboonchai, Jeffrey Posey, Willscott E. Naugler, Eugenio Montini, Markus Grompe
Journal: Molecular Therapy (2021)

Recombinant adeno-associated viral (rAAV) vectors are considered promising tools for gene therapy directed at the liver. Whereas rAAV is thought to be an episomal vector, its single-stranded DNA genome is prone to intra- and inter-molecular recombination leading to rearrangements and integration into the host cell genome. Here, we ascertained the integration frequency of rAAV in human hepatocytes transduced either ex vivo or in vivo and subsequently expanded in a mouse model of xenogeneic liver regeneration. Chromosomal rAAV integration events and vector integrity were determined using the capture-PacBio sequencing approach, a long-read next-generation sequencing method that has not previously been used for this purpose. Chromosomal integrations were found at a surprisingly high frequency of 1%-3% both in vitro and in vivo. Importantly, most of the inserted rAAV sequences were heavily rearranged and were accompanied by deletions of the host genomic sequence at the integration site.