tbuckley/cabot-search huggingface dataset:
Transcriptome Profiling Identifies TIGIT as a Marker of T‐Cell Exhaustion in Liver Cancer
Authors: Dmitrij Ostroumov, Steven Duong, Jessica Wingerath, Norman Woller, Michael P. Manns, Kai Timrott, Moritz Kleine, Wolf Ramackers, Stephanie Roessler, Sven Nahnsen, Stefan Czemmel, Oliver Dittrich‐Breiholz, Tobias Eggert, Florian Kühnel, Thomas C. Wirth
Journal: Hepatology (2020)

BACKGROUND AND AIMS Programmed death 1 (PD‐1) checkpoint inhibition has shown promising results in patients with hepatocellular carcinoma, inducing objective responses in approximately 20% of treated patients. The roles of other coinhibitory molecules and their individual contributions to T‐cell dysfunction in liver cancer, however, remain largely elusive. APPROACH AND RESULTS We performed a comprehensive mRNA profiling of cluster of differentiation 8 (CD8) T cells in a murine model of autochthonous liver cancer by comparing the transcriptome of naive, functional effector, and exhausted, tumor‐specific CD8 T cells. Subsequently, we functionally validated the role of identified genes in T‐cell exhaustion. Our results reveal a unique transcriptome signature of exhausted T cells and demonstrate that up‐regulation of the inhibitory immune receptor T‐cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibitor motif domains (TIGIT) represents a hallmark in the process of T‐cell exhaustion in liver cancer. Compared to PD‐1, expression of TIGIT more reliably identified exhausted CD8 T cells at different stages of their differentiation. In combination with PD‐1 inhibition, targeting of TIGIT with antagonistic antibodies resulted in synergistic inhibition of liver cancer growth in immunocompetent mice. Finally, we demonstrate expression of TIGIT on tumor‐infiltrating CD8 T cells in tissue samples of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma and identify two subsets of patients based on differential expression of TIGIT on tumor‐specific T cells. CONCLUSIONS Our transcriptome analysis provides a valuable resource for the identification of key pathways involved in T‐cell exhaustion in patients with liver cancer and identifies TIGIT as a potential target in checkpoint combination therapies.
Medical Education and Path to Residency in Ophthalmology in the COVID-19 Era: Perspective from Medical Student Educators
Authors: Andrew T. Duong, Sarah H. Van Tassel, Ana G. Alzaga Fernandez, Abha Amin, Nisha Chadha, Lora R. Dagi Glass, Inci Dersu, Anju Goyal, Emily B. Graubart, Zachary P. Elkin, Lisa Kelly, Pavlina S. Kemp, Daniel W. Knoch, Meredith Regina, Pearl S. Rosenbaum, Jamie B. Rosenberg, Prithvi S. Sankar, Grace Sun
Journal: Ophthalmology (2020)
Mcl-1 inhibition overcomes intrinsic and acquired Regorafenib resistance in Colorectal Cancer
Authors: Xiangping Song, Lin Shen, Jingshan Tong, Chaoyuan Kuang, Shan Zeng, Robert E Schoen, Jian Yu, Haiping Pei, Lin Zhang
Journal: Theranostics (2020)

Intrinsic and acquired resistance to targeted therapies is a significant clinical problem in cancer. We previously showed that resistance to regorafenib, a multi-kinase inhibitor for treating colorectal cancer (CRC) patients, can be caused by mutations in the tumor suppressor
AB0017 Antineutrophil cytoplasmic antibodies in rheumatoid arthritis patients
Authors: B Sonel, N Suldur, Þ Ataman, H Tutkak, N Duzgun, MB Atay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Antineutrophil cytoplasmic antibodies (ANCAs) have been suggested to occur in rheumatoid arthritis (RA), especially in patients with severe and longstanding disease. However in some studies no association was found between disease activity and ANCAs. <h3>Objectives</h3> To determine the occurrence of ANCAs in patients with RA and compare the clinical and laboratory activity parameters between ANCAs positivity and negativity. <h3>Methods</h3> Sera from 85 patients (mean age 50.5 years, 67 women and 18 men) with RA were included in study. Morning stiffness duration, pain intensity (Visual Analogue Scale), fatigue, tender and swollen joint counts (28 joints), systemic symptoms, patients and physicians general health assessment (Visual Analogue Scale), disease activity (DAS28), functional status (ACR) and disability (Health Assessment Questionnaire) were assessed of all patients. Besides the routine laboratory activity parameters, ANCA testing was performed by standard indirect immunofluorescence. Antibody against the cytoplasmic antigens proteinase-3 (PR3) and myeloperoxidase (MPO) were measured by enzyme-linked immunosorbent assay. <h3>Results</h3> ANCAs were found in 15 (17.6%) of patients with RA; 9 with atypical ANCA, 5 with perinuclear ANCA and 1 with cytoplasmic ANCA. Five of these 15 patients had vasculitis. None of the patients had Feltys syndrome, neutropenia or renal involvement. 4/5 patients with perinuclear ANCA and 1/9 patients with atypical ANCA had positive test result for MPO. None of the patients had PR3. There were no significant differences in ANCA positivity with respect to the duration of disease (mean 8.7 years), age, gender, clinical and laboratory inflammatory parameters except for the duration of morning stiffness (p = 0.04) and antinuclear antibody positivity (p = 0.001). <h3>Conclusion</h3> We observed that perinuclear ANCA pattern is specific for MPO but perinuclear and atypical ANCAs may not be associated with vasculitis in the presence of RA. Clinical significance of positive ANCAs was not justified with the findings of the study, as the number of patients with positive ANCA was few. <h3>References</h3> De Bandt M, Meyer O, Haim T, Kahn MF. Antineutrophil cytoplasmic antibodies in rheumatoid arthritis patients. Br J Rheumatol. 1996;35:38–43 Mustila A, Korpela M, Mustonen J, Helin H, et al. Perinuclear antineutrophil cytoplasmic antibody in rheumatoid arthritis. Arthritis Rheum. 1997;40(4):710–17 Coremans IEM, Hagen EC, Daha MR, et al. Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis. Arthritis Rheum. 1992;35(12):1466–75
The Rare YAP1 Subtype of SCLC Revisited in a Biobank of 39 Circulating Tumor Cell Patient Derived Explant Models: A Brief Report
Authors: Sarah M. Pearsall, Sam Humphrey, Mitchell Revill, Derrick Morgan, Kristopher K. Frese, Melanie Galvin, Alastair Kerr, Mathew Carter, Lynsey Priest, Fiona Blackhall, Kathryn L. Simpson, Caroline Dive
Journal: Journal of Thoracic Oncology (2020)

IntroductionRecent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell–derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity.MethodsYAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL.ResultsRNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells.ConclusionsYAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches.
AB0028 SELECTIVE DEPLETION OF PLASMA CELLS IN VIVOBASED ON SPECIFICITY OF SECRETED ANTIBODIES
Authors: Qingyu Cheng, Andreas Pelz, Bimba F. Hoyer, Laleh Khodadadi, Tobias Alexander, Gerd Rüdiger Burmester, Andreas Radbruch, Falk Hiepe
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Antibody-mediated diseases like allergies and chronic-inflammatory autoimmune diseases affect more than 10% of the human population, and for most, no cure is available. This is particularly true when pathogenic antibodies are secreted by long-lived plasma cells generated early in pathogenesis, which are refractory to conventional therapies. Therapeutic concepts for the generic ablation of plasma cells are currently being tested in clinical trials. These concepts target both plasma cells secreting pathogenic antibodies and those providing protective antibodies, i.e., humoral immunity. Efficient ablation of pathogenic plasma cells is inevitably accompanied by immunodeficiency and increased susceptibility to infection. <h3>Objectives:</h3> We studied the use of an antigen-antibody conjugate to label plasma cell in vivo with the antigen and selectively ablate those that secrete antibodies specific for the antigen. <h3>Methods:</h3> Balb/c mice were immunized with ovalbumin (OVA) and chicken gamma globulin (CGG), which resulted in the generation of OVA and CGG-specific long-lived plasma cells in the bone marrow. These mice were treated by a single intraperitoneal injection of a conjugate consisting of OVA and a monoclonal anti-CD138 antibody. The effect of this treatment on the long-lived plasma cells and antibody levels was analyzed by flow cytometry and ELISA, respectively. <h3>Results:</h3> The single injection of an OVA-anti-CD138 conjugate resulted in a significant depletion of OVA-specific plasma cells while CGG-specific plasma cells were not affected. The selective depletion of OVA-specific plasma cells also led to stable reduction of serum anti-OVA antibody levels; circulating anti-CGG antibody levels remained unchanged. <h3>Conclusion:</h3> The cellular antigen-affinity matrix strategy described here for the ablation of plasma cells <i>in vivo</i> according to the specificity of their antibodies enables a unique causative therapeutic approach in established antibody-mediated diseases without impairment of humoral immunity. <h3>References</h3> [1] Taddeo, A. et al. Eur J Immunol45, 317-319 (2015) <h3>Disclosure of Interests:</h3> Qingyu Cheng: None declared, Andreas Pelz: None declared, Bimba F. Hoyer: None declared, Laleh Khodadadi: None declared, Tobias Alexander: None declared, Gerd Rüdiger Burmester Consultant for: Roche, Sanofi-Genzyme, Speakers bureau: Roche, Sanofi-Genzyme, Andreas Radbruch: None declared, Falk Hiepe Grant/research support from: Sanofi, Consultant for: Sanofi, AstraZeneca, Morphosys, Janssen, GSK, Speakers bureau: Janssen, Roche, Pfizer
Opportunities and challenges in commercial pharmaceutical liposome applications
Authors: Gerard M. Jensen, Donald F. Hodgson
Journal: Advanced Drug Delivery Reviews (2020)

In the 1980s, the center of entrepreneurial activity for the application of liposome science to medicine took the form of a company called Vestar Inc. (which became NeXstar Pharmaceuticals Inc., and eventually a division of Gilead Sciences, with merger and acquisition activity). This company was formed from science initially developed at the California Institute of Technology and the City of Hope, and involving several other local academic and treatment centers. This company eventually produced two commercial liposomal therapeutics, and created a particular paradigm of formulation goals, formulation development, characterization, and production unique among the set of companies that emerged around the same time. A number of clinical candidates were also developed, but failed to achieve commercialization. Nevertheless, several of these provide still relevant lessons and guidance for the field. Key adaptations of this technology to lower cost applications have also been carried out and are examined.
Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention
Authors: Lisa M. Butler, Ylenia Perone, Jonas Dehairs, Leslie E. Lupien, Vincent de Laat, Ali Talebi, Massimo Loda, William B. Kinlaw, Johannes V. Swinnen
Journal: Advanced Drug Delivery Reviews (2020)

With the advent of effective tools to study lipids, including mass spectrometry-based lipidomics, lipids are emerging as central players in cancer biology. Lipids function as essential building blocks for membranes, serve as fuel to drive energy-demanding processes and play a key role as signaling molecules and as regulators of numerous cellular functions. Not unexpectedly, cancer cells, as well as other cell types in the tumor microenvironment, exploit various ways to acquire lipids and extensively rewire their metabolism as part of a plastic and context-dependent metabolic reprogramming that is driven by both oncogenic and environmental cues. The resulting changes in the fate and composition of lipids help cancer cells to thrive in a changing microenvironment by supporting key oncogenic functions and cancer hallmarks, including cellular energetics, promoting feedforward oncogenic signaling, resisting oxidative and other stresses, regulating intercellular communication and immune responses. Supported by the close connection between altered lipid metabolism and the pathogenic process, specific lipid profiles are emerging as unique disease biomarkers, with diagnostic, prognostic and predictive potential. Multiple preclinical studies illustrate the translational promise of exploiting lipid metabolism in cancer, and critically, have shown context dependent actionable vulnerabilities that can be rationally targeted, particularly in combinatorial approaches. Moreover, lipids themselves can be used as membrane disrupting agents or as key components of nanocarriers of various therapeutics. With a number of preclinical compounds and strategies that are approaching clinical trials, we are at the doorstep of exploiting a hitherto underappreciated hallmark of cancer and promising target in the oncologist's strategy to combat cancer.
Trust pays over £30m to 7 year old boy who was severely brain damaged at birth
Authors: Clare Dyer
Journal: BMJ (2020)

A 7 year old boy who was severely brain damaged at birth has received a settlement totalling more than £30m (€33.3m; $38.1m), one of the biggest negligence pay-outs ever made by the NHS.

His brain was starved of oxygen at birth, causing hypoxic ischaemic encephalopathy. This left him with an array of disabilities including a communication disorder, profound learning difficulties, severe developmental delay, challenging behavioural difficulties, and a complex sensory processing impairment.

Guy’s and St Thomas’ NHS Foundation Trust made an early admission of liability, and the NHS made interim payments enabling the family …
Age- and Weight-Adapted Dose of Prasugrel Versus Standard Dose of Ticagrelor in Patients With Acute Coronary Syndromes
Authors: Maurizio Menichelli, Franz-Josef Neumann, Gjin Ndrepepa, Katharina Mayer, Jochen Wöhrle, Isabell Bernlochner, Gert Richardt, Bernhard Witzenbichler, Dirk Sibbing, Senta Gewalt, Dominick J. Angiolillo, Shqipdona Lahu, Christian W. Hamm, Alexander Hapfelmeier, Dietmar Trenk, Karl-Ludwig Laugwitz, Heribert Schunkert, Stefanie Schüpke, Adnan Kastrati
Journal: Annals of Internal Medicine (2020)

The efficacy and safety of a reduced dose of prasugrel versus a standard dose of ticagrelor in elderly patients or those with a low body weight presenting with an acute coronary syndrome (ACS) are unknown.To investigate the effect of an age- and weight-adapted dose of prasugrel versus a standard dose of ticagrelor in patients with ACS. (ClinicalTrials.gov: NCT01944800).Prespecified analysis of the multicenter, randomized ISAR-REACT 5 trial.23 centers in Germany and Italy.3997 patients with ACS planned for invasive management.Participants were randomly assigned to receive a standard dose of ticagrelor or prasugrel (reduced dose in the elderly or low-weight group and standard dose in the neither elderly nor low-weight group).The efficacy end point was a composite of death, myocardial infarction, or stroke, and the safety end point was bleeding, both at 12 months.In the elderly or low-weight group, the efficacy end point occurred in 12.7% of patients assigned to receive prasugrel and 14.6% of those assigned to receive ticagrelor (hazard ratio [HR], 0.82 [95% CI, 0.60 to 1.14]); in the neither elderly nor low-weight group, the efficacy end point occurred in 4.8% of patients assigned to receive prasugrel and 7.3% of those assigned to receive ticagrelor (HR, 0.65 [CI, 0.48 to 0.88]; P for interaction > 0.2). In the elderly or low-weight group, Bleeding Academic Research Consortium type 3 to 5 bleeding occurred in 8.1% of patients assigned to receive prasugrel and 10.6% of those assigned to receive ticagrelor (HR, 0.72 [0.46 to 1.12]), and in 3.7% and 3.8%, respectively, of patients in the neither elderly nor low-weight group (HR, 0.98 [CI, 0.65 to 1.47]; P for interaction > 0.2).The study is a subgroup analysis.In elderly or low-weight patients with ACS, a reduced dose of prasugrel compared with the standard dose of ticagrelor is associated with maintained anti-ischemic efficacy while protecting these patients against the excess risk for bleeding.German Center for Cardiovascular Research and Deutsches Herzzentrum München.
Distinct effects of asthma and COPD comorbidity on disease expression and outcome in patients with COVID‐19
Authors: Jia Song, Ming Zeng, Hai Wang, Chuan Qin, Hong‐Yan Hou, Zi‐Yong Sun, San‐Peng Xu, Guo‐Ping Wang, Cui‐Lian Guo, Yi‐Ke Deng, Zhi‐Chao Wang, Jin Ma, Li Pan, Bo Liao, Zhi‐Hui Du, Qi‐Miao Feng, Yang Liu, Jun‐Gang Xie, Zheng Liu
Journal: Allergy (2020)

Abstract Background The impacts of chronic airway diseases on coronavirus disease 2019 (COVID‐19) are far from understood. Objective To explore the influence of asthma and chronic obstructive pulmonary disease (COPD) comorbidity on disease expression and outcomes, and the potential underlying mechanisms in COVID‐19 patients. Methods A total of 961 hospitalized COVID‐19 patients with a definite clinical outcome (death or discharge) were retrospectively enrolled. Demographic and clinical information were extracted from the medical records. Lung tissue sections from patients suffering from lung cancer were used for immunohistochemistry study of angiotensin‐converting enzyme II (ACE2) expression. BEAS‐2B cell line was stimulated with various cytokines. Results In this cohort, 21 subjects (2.2%) had COPD and 22 (2.3%) had asthma. After adjusting for confounding factors, COPD patients had higher risk of developing severe illness (OR: 23.433; 95% CI 1.525‐360.135; P &lt; .01) and acute respiratory distress syndrome (OR: 19.762; 95% CI 1.461‐267.369; P = .025) than asthmatics. COPD patients, particularly those with severe COVID‐19, had lower counts of CD4 + T and CD8 + T cells and B cells and higher levels of TNF‐α, IL‐2 receptor, IL‐10, IL‐8, and IL‐6 than asthmatics. COPD patients had increased, whereas asthmatics had decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL‐4 and IL‐13 downregulated, but TNF‐α, IL‐12, and IL‐17A upregulated ACE2 expression in BEAS‐2B cells. Conclusion Patients with asthma and COPD likely have different risk of severe COVID‐19, which may be associated with different ACE2 expression.
Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage
Authors: Xinghao Wang, Luz P. Blanco, Carmelo Carmona‐Rivera, Shuichiro Nakabo, Hege L. Pedersen, Zu‐Xi Yu, Mariana J. Kaplan
Journal: Arthritis & Rheumatology (2020)

Objective Gasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as pyroptosis. Recent reports have also implicated GSDMD in other mechanisms of cell death, including apoptosis, necroptosis, and NETosis. Given the role of dysregulated cell death in autoimmune syndromes such as systemic lupus erythematosus (SLE), this study was undertaken in a murine lupus model to investigate whether GSDMD plays a pathogenic role in systemic autoimmunity by promoting inflammatory cell death, leading to increased generation of nuclear autoantigens and autoantibodies. Methods An imiquimod‐induced model of SLE was tested in GSDMD −/− mice (n = 30), with wild‐type (WT) mice as controls (n = 34), on a C57BL/6 background. At the time of euthanasia, the mice were examined for serum autoantibodies, immune complex deposition, organ inflammation, immune dysregulation, and type I interferon responses. A model of pristane‐induced lung injury in GSDMD −/− mice (n = 7), with WT mice as controls (n = 10), was used to confirm the pulmonary phenotype. Regulation of various mechanisms of cell death by GSDMD was investigated in the mice. Results Unexpectedly, GSDMD −/− mice developed enhanced mortality, more severe renal and pulmonary inflammation, and exacerbated autoantibody production in response to imiquimod. Pulmonary involvement was also more severe in the absence of GSDMD in mice with pristane‐induced lung injury. Compared to WT mice, lack of GSDMD was associated with increased levels of circulating nuclear autoantigens ( P &lt; 0.01), anti–double‐stranded DNA autoantibodies ( P &lt; 0.01), tissue immune complex deposition ( P &lt; 0.05), expansion of myeloid cell subsets ( P &lt; 0.05), and enhanced B cell activation and plasma cell differentiation ( P = 0.001). Moreover, in the absence of GSDMD, enhanced autoantigen generation was associated with increased local induction of cell death in vivo. Conclusion GSDMD negatively regulates autoantigen generation and immune dysregulation in response to tissue injury and may play previously unappreciated protective roles in systemic autoimmunity.
Abstract 13813: Hepatic Extracellular Volume Fraction is Elevated in Patients With a Fontan Palliation: A Potential Marker of Liver Fibrosis Obtained During Cardiac Scanning
Authors: Lidija B McGrath, Ryan C Van Woerkom, Stephen B Heitner, Michael Jerosch-Herold, Craig S Broberg
Journal: Circulation (2019)

Objective: Extracellular volume (ECV) fraction, a marker of tissue remodeling due to excessive collagen deposition, can be quantified for the myocardium using contrast-enhanced T1 mapping with card...
Improved Outcome of Newly Diagnosed Childhood Mature B-Cell Lymphoma/Leukemia with High Tumor Burden Treated with BFM95-Based Protocol Combining Rituximab: A Report from Shanghai, China
Authors: Yang Fu, Hongsheng Wang, Xiaowen Zhai, Xiaowen Qian, Jianhua Meng, Hui Miao, Xiaohua Zhu, Yi Yu, Fengjuan Lu
Journal: Blood (2017)
Insight into impact of COVID-19 epidemic on tuberculosis burden in China
Authors: Hongguang Chen, Konglai Zhang
Journal: European Respiratory Journal (2020)

<b>In the early stage of the COVID-19 outbreak, it may have both positive and negative impact on tuberculosis control, and in the long run, it may reduce the disease burden of tuberculosis if COVID-19 could be effectively controlled</b>https://bit.ly/2ZObLzL
Abstract 14526: 8 Weeks Treprostinil Therapy Improves Function Capacity in Pulmonary Arterial Hypertension Patients at High Risk
Authors: Luo Qin, Zhihong Liu
Journal: Circulation (2018)

Background: Continuous dose-titration of IV or SC prostacyclin should be considered in severe PAH. SC Treprostinil (Trep) is preferably used in home setting, but the adverse events (AEs) mainly inf...
Disparities in Outcomes of Patients with Multiple Myeloma Based on Geographic Distance from NCI-Designated Cancer Centers: A SEER Based Analysis
Authors: Jacob Orme, Ronald S. Go, Shaji K Kumar, Angela Dispenzieri, Morie A. Gertz, Francis K Buadi, David Dingli, Nelson Leung, Martha Q Lacy, Prashant Kapoor, John A. Lust, Yi Lin, Stephen J. Russell, Suzanne R. Hayman, Steven Zeldenrust, Taxiarchis Kourelis, Rahma Warsame, Robert A Kyle, S. Vincent Rajkumar, Wilson I Gonsalves
Journal: Blood (2017)