tbuckley/cabot-search huggingface dataset:
Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA
Authors: Christopher J. Holland, Rory M. Crean, Johanne M. Pentier, Ben de Wet, Angharad Lloyd, Velupillai Srikannathasan, Nikolai Lissin, Katy A. Lloyd, Thomas H. Blicher, Paul J. Conroy, Miriam Hock, Robert J. Pengelly, Thomas E. Spinner, Brian Cameron, Elizabeth A. Potter, Anitha Jeyanthan, Peter E. Molloy, Malkit Sami, Milos Aleksic, Nathaniel Liddy, Ross A. Robinson, Stephen Harper, Marco Lepore, Chris R. Pudney, Marc W. van der Kamp, Pierre J. Rizkallah, Bent K. Jakobsen, Annelise Vuidepot, David K. Cole
Journal: Journal of Clinical Investigation (2020)

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents.
Cancer in the time of COVID-19: expert opinion on how to adapt current practice
Authors: Jo Raskin, Marnix Lebeer, Charlotte De Bondt, Reinier Wener, Annelies Janssens, Jan P. van Meerbeeck
Journal: European Respiratory Journal (2020)

<b>Our current thoracic oncology practice could/should be adapted to the COVID-19 pandemic by reducing time in hospital and patient contacts with healthcare workers, whilst maintaining quality of care. This letter offers expert advice on how to do so.</b>https://bit.ly/2JR2IoT
Prevention of COVID-19 in patients with inflammatory bowel disease in Wuhan, China
Authors: Ping An, Mengyao Ji, Haixia Ren, Juan Su, Nik Sheng Ding, Jian Kang, Anning Yin, Qian Zhou, Linyong Shen, Liang Zhao, Xiaoda Jiang, Yong Xiao, Wei Tan, Xiaoguang Lv, Jiao Li, Shuzhong Liu, Jing Zhou, Hongbin Chen, Yaqing Xu, Jun Liu, Mingkai Chen, Jiwang Cao, Zhongyin Zhou, Lei Shen, Shiyun Tan, Honggang Yu, Weiguo Dong, Yijuan Ding
Journal: The Lancet. Gastroenterology & hepatology (2020)

Viral screening before initiation of biologics in patients with inflammatory bowel disease during the COVID-19 outbreakWe read with interest the Comment by Ren Mao and colleagues on the implications of coronavirus disease 2019 (COVID-19) in patients with pre-existing digestive diseases, and the strategies implemented in China to restrict the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with inflammatory bowel disease. 1 We agree with the current evidence that does not support drug suspension and also with the European Crohn's and Colitis Organisation COVID-19We declare no competing interests.
Haploid male germ cells—the Grand Central Station of protein transport
Authors: Christiane Pleuger, Mari S Lehti, Jessica EM Dunleavy, Daniela Fietz, Moira K O’Bryan
Journal: Human Reproduction Update (2020)

The precise movement of proteins and vesicles is an essential ability for all eukaryotic cells. Nowhere is this more evident than during the remarkable transformation that occurs in spermiogenesis-the transformation of haploid round spermatids into sperm. These transformations are critically dependent upon both the microtubule and the actin cytoskeleton, and defects in these processes are thought to underpin a significant percentage of human male infertility.This review is aimed at summarising and synthesising the current state of knowledge around protein/vesicle transport during haploid male germ cell development and identifying knowledge gaps and challenges for future research. To achieve this, we summarise the key discoveries related to protein transport using the mouse as a model system. Where relevant, we anchored these insights to knowledge in the field of human spermiogenesis and the causality of human male infertility.Relevant studies published in English were identified using PubMed using a range of search terms related to the core focus of the review-protein/vesicle transport, intra-flagellar transport, intra-manchette transport, Golgi, acrosome, manchette, axoneme, outer dense fibres and fibrous sheath. Searches were not restricted to a particular time frame or species although the emphasis within the review is on mammalian spermiogenesis.Spermiogenesis is the final phase of sperm development. It results in the transformation of a round cell into a highly polarised sperm with the capacity for fertility. It is critically dependent on the cytoskeleton and its ability to transport protein complexes and vesicles over long distances and often between distinct cytoplasmic compartments. The development of the acrosome covering the sperm head, the sperm tail within the ciliary lobe, the manchette and its role in sperm head shaping and protein transport into the tail, and the assembly of mitochondria into the mid-piece of sperm, may all be viewed as a series of overlapping and interconnected train tracks. Defects in this redistribution network lead to male infertility characterised by abnormal sperm morphology (teratozoospermia) and/or abnormal sperm motility (asthenozoospermia) and are likely to be causal of, or contribute to, a significant percentage of human male infertility.A greater understanding of the mechanisms of protein transport in spermiogenesis offers the potential to precisely diagnose cases of male infertility and to forecast implications for children conceived using gametes containing these mutations. The manipulation of these processes will offer opportunities for male-based contraceptive development. Further, as increasingly evidenced in the literature, we believe that the continuous and spatiotemporally restrained nature of spermiogenesis provides an outstanding model system to identify, and de-code, cytoskeletal elements and transport mechanisms of relevance to multiple tissues.
In‐vivo diagnostic test allergens in Europe: A call to action and proposal for recovery plan—An EAACI position paper
Authors: Ludger Klimek, Hans J. Hoffmann, Ayse F. Kalpaklioglu, Pascal Demoly, Ioana Agache, Todor A. Popov, Antonella Muraro, Peter Schmid‐Grendelmeier, Sergio Bonini, Andreas Bonertz, Vera Mahler, Stefan Vieths, Oliver Pfaar, Torsten Zuberbier, Marek Jutel, Carsten Schmidt‐Weber, Peter W. Hellings, Sten Dreborg, Matteo Bonini, Helen A. Brough, Jean Bousquet, Karin Hoffmann‐Sommergruber, Oscar Palomares, Markus Ollert, Mohamed H. Shamji, Victoria Cardona
Journal: Allergy (2020)

Abstract Diagnostic allergens are defined as medicinal products in the EU. Marketing authorization by national authorities is necessary; however, diagnostic allergens are not homogeneously regulated in different EU member states. Allergen manufacturers argue with increasing costs forcing them to continuously reduce the diagnostic allergen portfolios offered to allergists. In contrast, EAACI and national European Allergy Societies see the need for the availability of a wide range of high‐quality diagnostic allergens for in vivo diagnosis of IgE‐mediated allergies not only covering predominant but also less frequent allergen sources. In a recent EAACI task force survey, the current practice of allergy diagnosis was shown to rely on skin tests as first option in almost 2/3 of all types of allergic diseases and in 90% regarding respiratory allergies. With the need to ensure the availability of high‐quality diagnostic allergens in the EU, an action plan has been set up by EAACI to analyse the current regulatory demands in EU member states and to define possible solutions stated in this document: (a) simplification of authorization for diagnostic allergens; (b) specific regulation of special types of diagnostic allergens; (c) new models beyond the current model of homologous groups; (d) simplification of pharmacovigilance reporting; (e) reduction of regulation fees for diagnostic allergens; (f) reimbursement for diagnostic allergens. Joining forces of allergists, manufacturers and authorities are of high importance to ensure remaining relevant allergens in the EU markets to facilitate a sustainable and comprehensive service for the diagnosis and treatment of allergic diseases.
Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting
Authors: Domenico Viola, Ada Dona, Enrico Caserta, Estelle Troadec, Francesca Besi, Tinisha McDonald, Lucy Ghoda, Emine Gulsen Gunes, James F. Sanchez, Jihane Khalife, Marianna Martella, Chatchada Karanes, Myo Htut, Xiuli Wang, Michael Rosenzweig, Arnab Chowdhury, Douglas Sborov, Rodney R. Miles, Paul J. Yazaki, Todd Ebner, Craig C. Hofmeister, Stephen J. Forman, Steven T. Rosen, Guido Marcucci, John Shively, Jonathan J. Keats, Amrita Krishnan, Flavia Pichiorri
Journal: Leukemia (2020)
Abstract 16899: Fully-Automated Left Ventricle Segmentation Using a Dilated and Adversarial Deep Learning Architecture
Authors: Heming Yao, Jonathan Gryak, Harm Derksen, Anil K Attili, Brahmajee K Nallamothu, Kayvan Najarian
Journal: Circulation (2018)

Introduction: Cardiovascular magnetic resonance (CMR) imaging is currently the gold-standard to analyze cardiac morphology and evaluate global and regional left ventricle (LV) function. Quantitative parameters such as ejection fraction (EF) and LV mass are important indicators for diagnosis and associated with morbidity and mortality. In practice, the manual or semi-automatic delineations of LV contours for function evaluation are time-consuming and prone to intra- and inter-observer variability. The objective of this study is to develop an accurate and fully-automatic LV segmentation method for CMR slices in short axis using deep learning techniques. Methods: In this study, we trained a model using the LV2011 training dataset, which contains 100 cases of patients with myocardial infarction from multiple MR scanner system using balanced steady-state free precession. We developed a novel fully convolutional network (FCN) with dilated convolutions for pixel-wise prediction. An adversarial network is added to enforce high-order consistency. Furthermore, a guided active contour model is deployed as a post-processing method that considers the intensity homogeneities and boundary smoothness of segmented components. The similarity between the automatic segmentation from our model and the manual segmentation are evaluated using Jaccard index and Hausdorff distance (HD). Results: On the LV2011 test dataset, our model achieved a Jaccard index of 0.77 and HD of 4.12 mm, outperforming existing fully-automatic methods. Examples of segmentation results are shown in Figure 1. The clinical parameter estimations also have high reliability. The correlations between the end-diastolic volume, end-systolic volume, EF, and LV mass, estimated from automatic segmentation and that from manual segmentation on the test dataset, are 0.99, 0.99, 0.93, and 0.96, respectively. Conclusions: Our results demonstrate that the proposed method obtains accurate segmentation and is robust over cases of high variability.
Management of Acute Myocardial Infarction During the COVID-19 Pandemic
Authors: Ehtisham Mahmud, Harold L. Dauerman, Frederick G.P. Welt, John C. Messenger, Sunil V. Rao, Cindy Grines, Amal Mattu, Ajay J. Kirtane, Rajiv Jauhar, Perwaiz Meraj, Ivan C. Rokos, John S. Rumsfeld, Timothy D. Henry
Journal: Journal of the American College of Cardiology (2020)
Efficacy of a novel self-assembling peptide hemostatic gel as rescue therapy for refractory acute gastrointestinal bleeding
Authors: Germana de Nucci, Raffaella Reati, Ilaria Arena, Cristina Bezzio, Massimo Devani, Cristina della Corte, Daniela Morganti, Enzo Domenico Mandelli, Barbara Omazzi, Davide Redaelli, Simone Saibeni, Marco Dinelli, Gianpiero Manes
Journal: Endoscopy (2020)

Abstract Background Acute gastrointestinal bleeding (AGIB) results in significant morbidity and mortality. Topical hemostatic products have been developed for endoscopic use to help in the management of difficult bleeding. Our aim was to demonstrate the ease of use, safety, and efficacy of PuraStat, a novel hemostat, to control AGIB. Methods We describe 77 patients (41 men) who were treated for acute upper and lower AGIB in a 2-year period. In 50 patients, bleeding occurred as a complication of a previous endoscopic procedure, predominantly endoscopic mucosal resection (EMR) and endoscopic retrograde cholangiopancreatography (ERCP); however, in the other 27 patients, it derived from peptic ulcers, angiodysplasia, cancers, and surgical anastomoses. Bleeding was spurting in 13 of the 77 patients and oozing in 64. PuraStat was used after the failure of at least two conventional hemostatic methods. Results A mean of 2.6 conventional hemostatic methods had been attempted prior to the application of PuraStat. PuraStat achieved successful hemostasis in 90.9 % of patients. In 41 patients, once hemostasis was obtained with PuraStat, endoscopists further stabilized hemostasis by using at least one additional method. Recurrence of bleeding was observed in eight patients (10.4 %). In 16 patients with intraprocedural bleeding, it was possible to complete the procedures (14 EMR, 2 ERCP) after PuraStat hemostasis. No adverse events related to PuraStat were recorded. Conclusions PuraStat is feasible, safe, and effective in controlling different types of gastrointestinal hemorrhage after failure of conventional hemostatic methods. Its application also does not hinder continuing endotherapy.
Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial
Authors: Robert Jotte, Federico Cappuzzo, Ihor Vynnychenko, Daniil Stroyakovskiy, Delvys Rodríguez-Abreu, Maen Hussein, Ross Soo, Henry J. Conter, Toshiyuki Kozuki, Kuan-Chieh Huang, Vilma Graupner, Shawn W. Sun, Tien Hoang, Helen Jessop, Mark McCleland, Marcus Ballinger, Alan Sandler, Mark A. Socinski
Journal: Journal of Thoracic Oncology (2020)

Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC.A total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported.PFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60-0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73-1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1-high subgroup (HR = 0.48, 95% CI: 0.29-0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively.Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms.
Effect Size and Blinding in Lumateperone Trial—Reply
Authors: Christoph U. Correll, Hassan D. Lakkis, Kimberly E. Vanover
Journal: JAMA Psychiatry (2020)

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Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure
Authors: Wei Zou, Nidhi Rohatgi, Jonathan R Brestoff, John R Moley, Yongjia Li, Jesse W Williams, Yael Alippe, Hua Pan, Terri A Pietka, Gabriel Mbalaviele, Elizabeth P Newberry, Nicholas O Davidson, Anwesha Dey, Kooresh I Shoghi, Richard D Head, Samuel A Wickline, Gwendalyn J Randolph, Nada A Abumrad, Steven L Teitelbaum
Journal: Journal of Clinical Investigation (2020)

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells' inflammatory phenotype may impact obesity and its complications.
Novel insight into the regulatory roles of diverse RNA modifications: Re-defining the bridge between transcription and translation
Authors: Hanhan Shi, Peiwei Chai, Renbing Jia, Xianqun Fan
Journal: Molecular Cancer (2020)

Abstract RNA modifications can be added or removed by a variety of enzymes that catalyse the necessary reactions, and these modifications play roles in essential molecular mechanisms. The prevalent modifications on mRNA include N6-methyladenosine (m 6 A), N1-methyladenosine (m 1 A), 5-methylcytosine (m 5 C), 5-hydroxymethylcytosine (hm 5 C), pseudouridine (Ψ), inosine (I), uridine (U) and ribosemethylation (2’-O-Me). Most of these modifications contribute to pre-mRNA splicing, nuclear export, transcript stability and translation initiation in eukaryotic cells. By participating in various physiological processes, RNA modifications also have regulatory roles in the pathogenesis of tumour and non-tumour diseases. We discussed the physiological roles of RNA modifications and associated these roles with disease pathogenesis. Functioning as the bridge between transcription and translation, RNA modifications are vital for the progression of numerous diseases and can even regulate the fate of cancer cells.
COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up
Authors: Behnood Bikdeli, Mahesh V. Madhavan, David Jimenez, Taylor Chuich, Isaac Dreyfus, Elissa Driggin, Caroline Der Nigoghossian, Walter Ageno, Mohammad Madjid, Yutao Guo, Liang V. Tang, Yu Hu, Jay Giri, Mary Cushman, Isabelle Quéré, Evangelos P. Dimakakos, C. Michael Gibson, Giuseppe Lippi, Emmanuel J. Favaloro, Jawed Fareed, Joseph A. Caprini, Alfonso J. Tafur, John R. Burton, Dominic P. Francese, Elizabeth Y. Wang, Anna Falanga, Claire McLintock, Beverley J. Hunt, Alex C. Spyropoulos, Geoffrey D. Barnes, John W. Eikelboom, Ido Weinberg, Sam Schulman, Marc Carrier, Gregory Piazza, Joshua A. Beckman, P. Gabriel Steg, Gregg W. Stone, Stephan Rosenkranz, Samuel Z. Goldhaber, Sahil A. Parikh, Manuel Monreal, Harlan M. Krumholz, Stavros V. Konstantinides, Jeffrey I. Weitz, Gregory Y.H. Lip
Journal: Journal of the American College of Cardiology (2020)
Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs
Authors: Tomoya Muto, Callum S. Walker, Kwangmin Choi, Kathleen Hueneman, Molly A. Smith, Zartash Gul, Guillermo Garcia-Manero, Averil Ma, Yi Zheng, Daniel T. Starczynowski
Journal: Nature Immunology (2020)
Covid-19: Mental health consequences of pandemic need urgent research, paper advises
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Research is urgently needed to help understand the mental health consequences of the covid-19 pandemic on healthcare workers and the public, researchers have argued in a position paper published in the Lancet Psychiatry. 1 The paper, funded by the Academy of Medical Sciences, looks at the psychological, social, and neuroscientific effects of covid-19.It warns of major adverse consequences of the pandemic, including increased social isolation and loneliness, which are "strongly associated with anxiety, depression, self-harm, and suicide attempts across the lifespan."The authors suggest a number of immediate and longer term actions to mitigate the mental health consequences of this pandemic and any similar future situations, including better monitoring systems and rapidly rolling out evidence based programmes and treatments that can be accessed remotely.