tbuckley/cabot-search huggingface dataset:
FRI0008 Difficult to treat rheumatoids respond to leflunomide
Authors: FM Erkeller-Yuksel, JA Griffin
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Leflunomide (LEF) is a new disease modifying agent for rheumatoid arthritis (RA). It was successful in treating relatively recent onset rheumatoid patients with a good safety record.<sup>1</sup> <h3>Objectives</h3> Our aim was to assess the safety and efficacy of LEF in difficult to treat and chronic rheumatoid patients in a district general hospital. <h3>Methods</h3> Patients with difficult to treat RA (n = 39) were commenced on LEF. Patients were followed every 4 for 6 months for side effect profiles and efficacy recordings. We documented all side effects of LEF, routine blood test results and blood pressure measurements. Pre-treatment and 6th month erythrocyte sedimentation rate (ESR) and haemoglobin (Hb) levels, patients' and doctors' global disease activity Visual Analogue Scores (VAS) were Statistically compared. <h3>Results</h3> Mean age of patients was 48+14 and duration of disease was 13+10 years. Combination of methotrexate with LEF was the choice of treatment for 12 patients. Until now 25 patients completed 6 months evaluation and 9 out of 39 patients discontinued LEF due to side effects or infections. 6 further patients discontinued LEF after 6 months. Alopecia, diarrhoea and rash were the most common side effects (28%, 26% and 23% respectively). The most serious adverse effect was sensory neuropathy of the lower limbs in a young male patient. This occurred within 10 months of LEF treatment and showed some improvement 2 months after discontinuation. Another elderly male was admitted to hospital twice with severe abdominal pains and diverticulitis. Patients felt better on LEF treatment and showed significant improvement in reduction of ESR (p &lt; 0.02), increase of Hb (p &lt; 0.02) and a reduction of VAS of patients' (0.0001) and doctors' (p &lt; 0.0001) global disease activity over a 6 month period (Wilcox Rank Sum Test). Due to clinical improvement we were able to stop or reduce dosage of other concominant treatment. <h3>Conclusion</h3> In conclusion LEF was reasonably well tolerated by difficult to treat rheumatoids even though side effects were more frequent than published studies (1). The clinical response was good considering the long disease duration and history of poor response to treatment in our group. <h3>Reference</h3> Emery P, Breedvekd FC, Lemmek EM, Kaltwasser JP, Dawes PT, <i>et al</i>. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology 2000;39:655–65
Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates
Authors: Edward E. Walsh, Robert W. Frenck, Ann R. Falsey, Nicholas Kitchin, Judith Absalon, Alejandra Gurtman, Stephen Lockhart, Kathleen Neuzil, Mark J. Mulligan, Ruth Bailey, Kena A. Swanson, Ping Li, Kenneth Koury, Warren Kalina, David Cooper, Camila Fontes-Garfias, Pei-Yong Shi, Özlem Türeci, Kristin R. Tompkins, Kirsten E. Lyke, Vanessa Raabe, Philip R. Dormitzer, Kathrin U. Jansen, Uğur Şahin, William C. Gruber
Journal: New England Journal of Medicine (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resulting disease, coronavirus disease 2019 (Covid-19), have spread to millions of persons worldwide. Multiple vaccine candidates are under development, but no vaccine is currently available. Interim safety and immunogenicity data about the vaccine candidate BNT162b1 in younger adults have been reported previously from trials in Germany and the United States.In an ongoing, placebo-controlled, observer-blinded, dose-escalation, phase 1 trial conducted in the United States, we randomly assigned healthy adults 18 to 55 years of age and those 65 to 85 years of age to receive either placebo or one of two lipid nanoparticle-formulated, nucleoside-modified RNA vaccine candidates: BNT162b1, which encodes a secreted trimerized SARS-CoV-2 receptor-binding domain; or BNT162b2, which encodes a membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. Trial groups were defined according to vaccine candidate, age of the participants, and vaccine dose level (10 μg, 20 μg, 30 μg, and 100 μg). In all groups but one, participants received two doses, with a 21-day interval between doses; in one group (100 μg of BNT162b1), participants received one dose.A total of 195 participants underwent randomization. In each of 13 groups of 15 participants, 12 participants received vaccine and 3 received placebo. BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2-neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples.The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates in younger and older adults, added to earlier interim safety and immunogenicity data regarding BNT162b1 in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2-3 safety and efficacy evaluation. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).
Second-Strand Synthesis-Based Massively Parallel scRNA-Seq Reveals Cellular States and Molecular Features of Human Inflammatory Skin Pathologies
Authors: Travis K. Hughes, Marc H. Wadsworth, Todd M. Gierahn, Tran Do, David Weiss, Priscila R. Andrade, Feiyang Ma, Bruno J. de Andrade Silva, Shuai Shao, Lam C. Tsoi, Jose Ordovas-Montanes, Johann E. Gudjonsson, Robert L. Modlin, J. Christopher Love, Alex K. Shalek
Journal: Immunity (2020)

High-throughput single-cell RNA-sequencing (scRNA-seq) methodologies enable characterization of complex biological samples by increasing the number of cells that can be profiled contemporaneously. Nevertheless, these approaches recover less information per cell than low-throughput strategies. To accurately report the expression of key phenotypic features of cells, scRNA-seq platforms are needed that are both high fidelity and high throughput. To address this need, we created Seq-Well S3 ("Second-Strand Synthesis"), a massively parallel scRNA-seq protocol that uses a randomly primed second-strand synthesis to recover complementary DNA (cDNA) molecules that were successfully reverse transcribed but to which a second oligonucleotide handle, necessary for subsequent whole transcriptome amplification, was not appended due to inefficient template switching. Seq-Well S3 increased the efficiency of transcript capture and gene detection compared with that of previous iterations by up to 10- and 5-fold, respectively. We used Seq-Well S3 to chart the transcriptional landscape of five human inflammatory skin diseases, thus providing a resource for the further study of human skin inflammation.
SARS-CoV-2 vaccine development, access, and equity
Authors: Jerome H. Kim
Journal: The Journal of Experimental Medicine (2020)

Over the past 9 mo, with 34 million infections and 1 million deaths, the COVID-19 pandemic has levied a grisly toll. Some countries, through political will and social organization, have successfully reduced the number of infections and deaths, but the global scale of loss reflects the difficulty of translating these approaches in other countries. An effective SARS-CoV-2 vaccine presents a technological solution to the failure of social and political ones. Vaccines are, however, not a silver bullet, but a safe, cost-effective, and globally applicable tool that will require a substantial effort-cooperation, commitment, time, and funding-to be effective.
Tc17 CD8+ T cells accumulate in murine atherosclerotic lesions, but do not contribute to early atherosclerosis development
Authors: Janine van Duijn, Maaike J M de Jong, Naomi Benne, Romain J T Leboux, Marieke E van Ooijen, Nicky Kruit, Amanda C Foks, Wim Jiskoot, Ilze Bot, Johan Kuiper, Bram Slütter
Journal: Cardiovascular Research (2020)

CD8+ T cells can differentiate into subpopulations that are characterized by a specific cytokine profile, such as the Tc17 population that produces interleukin-17. The role of this CD8+ T-cell subset in atherosclerosis remains elusive. In this study, we therefore investigated the contribution of Tc17 cells to the development of atherosclerosis.
Trends in 3D bioprinting for esophageal tissue repair and reconstruction
Authors: Wissam Farhat, François Chatelain, Auriane Marret, Lionel Faivre, Lousineh Arakelian, Pierre Cattan, Alexandra Fuchs
Journal: Biomaterials (2020)

In esophageal pathologies, such as esophageal atresia, cancers, caustic burns, or post-operative stenosis, esophageal replacement is performed by using parts of the gastrointestinal tract to restore nutritional autonomy. However, this surgical procedure most often does not lead to complete functional recovery and is instead associated with many complications resulting in a decrease in the quality of life and survival rate. Esophageal tissue engineering (ETE) aims at repairing the defective esophagus and is considered as a promising therapeutic alternative. Noteworthy progress has recently been made in the ETE research area but strong challenges remain to replicate the structural and functional integrity of the esophagus with the approaches currently being developed. Within this context, 3D bioprinting is emerging as a new technology to facilitate the patterning of both cellular and acellular bioinks into well-organized 3D functional structures. Here, we present a comprehensive overview of the recent advances in tissue engineering for esophageal reconstruction with a specific focus on 3D bioprinting approaches in ETE. Current biofabrication techniques and bioink features are highlighted, and these are discussed in view of the complexity of the native esophagus that the designed substitute needs to replace. Finally, perspectives on recent strategies for fabricating other tubular organ substitutes via 3D bioprinting are discussed briefly for their potential in ETE applications.
Amino Acid Sensing in Metabolic Homeostasis and Health
Authors: Xiaoming Hu, Feifan Guo
Journal: Endocrine Reviews (2020)

Abstract Sensing and responding to changes in nutrient levels, including those of glucose, lipids, and amino acids, by the body is necessary for survival. Accordingly, perturbations in nutrient sensing are tightly linked with human pathologies, particularly metabolic diseases such as obesity, type 2 diabetes mellitus, and other complications of metabolic syndromes. The conventional view is that amino acids are fundamental elements for protein and peptide synthesis, while recent studies have revealed that amino acids are also important bioactive molecules that play key roles in signaling pathways and metabolic regulation. Different pathways that sense intracellular and extracellular levels of amino acids are integrated and coordinated at the organismal level, and, together, these pathways maintain whole metabolic homeostasis. In this review, we discuss the studies describing how important sensing signals respond to amino acid availability and how these sensing mechanisms modulate metabolic processes, including energy, glucose, and lipid metabolism. We further discuss whether dysregulation of amino acid sensing signals can be targeted to promote metabolic disorders, and discuss how to translate these mechanisms to treat human diseases. This review will help to enhance our overall understanding of the correlation between amino acid sensing and metabolic homeostasis, which have important implications for human health.
A Comprehensive Subcellular Atlas of the Toxoplasma Proteome via hyperLOPIT Provides Spatial Context for Protein Functions
Authors: Konstantin Barylyuk, Ludek Koreny, Huiling Ke, Simon Butterworth, Oliver M. Crook, Imen Lassadi, Vipul Gupta, Eelco Tromer, Tobias Mourier, Tim J. Stevens, Lisa M. Breckels, Arnab Pain, Kathryn S. Lilley, Ross F. Waller
Journal: Cell Host & Microbe (2020)

Apicomplexan parasites cause major human disease and food insecurity. They owe their considerable success to highly specialized cell compartments and structures. These adaptations drive their recognition, nondestructive penetration, and elaborate reengineering of the host's cells to promote their growth, dissemination, and the countering of host defenses. The evolution of unique apicomplexan cellular compartments is concomitant with vast proteomic novelty. Consequently, half of apicomplexan proteins are unique and uncharacterized. Here, we determine the steady-state subcellular location of thousands of proteins simultaneously within the globally prevalent apicomplexan parasite Toxoplasma gondii. This provides unprecedented comprehensive molecular definition of these unicellular eukaryotes and their specialized compartments, and these data reveal the spatial organizations of protein expression and function, adaptation to hosts, and the underlying evolutionary trajectories of these pathogens.
Contrasting Associations Between Diabetes and Cardiovascular Mortality Rates in Low-, Middle-, and High-Income Countries: Cohort Study Data From 143,567 Individuals in 21 Countries in the PURE Study
Authors: Ranjit Mohan Anjana, Viswanathan Mohan, Sumathy Rangarajan, Hertzel C. Gerstein, Ulagamadesan Venkatesan, Patrick Sheridan, Gilles R. Dagenais, Scott A. Lear, Koon Teo, Kubilay Karsidag, Khalid F. Alhabib, Khalid Yusoff, Noorhassim Ismail, Prem K. Mony, Patricio Lopez-Jaramillo, Jephat Chifamba, Lia M. Palileo-Villanueva, Romaina Iqbal, Afzalhussein Yusufali, Iolanthe M. Kruger, Annika Rosengren, Ahmad Bahonar, Katarzyna Zatonska, Karen Yeates, Rajeev Gupta, Wei Li, Lihua Hu, M. Omar Rahman, P.V.M. Lakshmi, Thomas Iype, Alvaro Avezum, Rafael Diaz, Fernando Lanas, Salim Yusuf
Journal: Diabetes Care (2020)

OBJECTIVE We aimed to compare cardiovascular (CV) events, all-cause mortality, and CV mortality rates among adults with and without diabetes in countries with differing levels of income. RESEARCH DESIGN AND METHODS The Prospective Urban Rural Epidemiology (PURE) study enrolled 143,567 adults aged 35–70 years from 4 high-income countries (HIC), 12 middle-income countries (MIC), and 5 low-income countries (LIC). The mean follow-up was 9.0 ± 3.0 years. RESULTS Among those with diabetes, CVD rates (LIC 10.3, MIC 9.2, HIC 8.3 per 1,000 person-years, P &amp;lt; 0.001), all-cause mortality (LIC 13.8, MIC 7.2, HIC 4.2 per 1,000 person-years, P &amp;lt; 0.001), and CV mortality (LIC 5.7, MIC 2.2, HIC 1.0 per 1,000 person-years, P &amp;lt; 0.001) were considerably higher in LIC compared with MIC and HIC. Within LIC, mortality was higher in those in the lowest tertile of wealth index (low 14.7%, middle 10.8%, and high 6.5%). In contrast to HIC and MIC, the increased CV mortality in those with diabetes in LIC remained unchanged even after adjustment for behavioral risk factors and treatments (hazard ratio [95% CI] 1.89 [1.58–2.27] to 1.78 [1.36–2.34]). CONCLUSIONS CVD rates, all-cause mortality, and CV mortality were markedly higher among those with diabetes in LIC compared with MIC and HIC with mortality risk remaining unchanged even after adjustment for risk factors and treatments. There is an urgent need to improve access to care to those with diabetes in LIC to reduce the excess mortality rates, particularly among those in the poorer strata of society.
Regulation of single-cell genome organization into TADs and chromatin nanodomains
Authors: Quentin Szabo, Axelle Donjon, Ivana Jerković, Giorgio L. Papadopoulos, Thierry Cheutin, Boyan Bonev, Elphège P. Nora, Benoit G. Bruneau, Frédéric Bantignies, Giacomo Cavalli
Journal: Nature Genetics (2020)
International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)
Authors: María-Victoria Mateos, Shaji Kumar, Meletios A. Dimopoulos, Verónica González-Calle, Efstathios Kastritis, Roman Hajek, Carlos Fernández De Larrea, Gareth J. Morgan, Giampaolo Merlini, Hartmut Goldschmidt, Catarina Geraldes, Alessandro Gozzetti, Charalampia Kyriakou, Laurent Garderet, Markus Hansson, Elena Zamagni, Dorotea Fantl, Xavier Leleu, Byung-Su Kim, Graça Esteves, Heinz Ludwig, Saad Usmani, Chang-Ki Min, Ming Qi, Jon Ukropec, Brendan M. Weiss, S. Vincent Rajkumar, Brian G. M. Durie, Jesús San-Miguel
Journal: Blood Cancer Journal (2020)

Abstract Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein &gt;2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio &gt;20 (HR: 2.7), and marrow plasma cell infiltration &gt;20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.
Energy metabolism disorders and potential therapeutic drugs in heart failure
Authors: Yanan He, Wei Huang, Chen Zhang, Lumeng Chen, Runchun Xu, Nan Li, Fang Wang, Li Han, Ming Yang, Dingkun Zhang
Journal: Acta Pharmaceutica Sinica B (2020)

Heart failure (HF) is a global public health problem with high morbidity and mortality. A large number of studies have shown that HF is caused by severe energy metabolism disorders, which result in an insufficient heart energy supply. This deficiency causes cardiac pump dysfunction and systemic energy metabolism failure, which determine the development of HF and recovery of heart. Current HF therapy acts by reducing heart rate and cardiac preload and afterload, treating the HF symptomatically or delaying development of the disease. Drugs aimed at cardiac energy metabolism have not yet been developed. In this review, we outline the main characteristics of cardiac energy metabolism in healthy hearts, changes in metabolism during HF, and related pathways and targets of energy metabolism. Finally, we discuss drugs that improve cardiac function via energy metabolism to provide new research ideas for the development and application of drugs for treating HF.
Abstract 11627: Eosinophil Attenuates Cardiac Hypertrophy, Apoptosis and Fibrosis by Releasing Eosinophil Cationic Protein and Il-4
Authors: Chongzhe Yang, Jie Li, Feng Liu, Peter Libby, Guoping Shi
Journal: Circulation (2018)

Introduction: Clinic studies and experimental models demonstrate that cardiac hypertrophy and heart failure involve cardiac cell apoptosis, fibrosis, and immune cell interactions. Eosinophil is a p...
HP0030 An investigation of the effect of education or education in combination with physical training among women with osteoporosis
Authors: TS Søyseth, V Søyseth
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Introduction</h3> Pain and fear of fractures are very common among osteoporotics reducing their activity of daily living and quality of life. We have investigated the effect of education or education in combination with physical training on pain experience in osteoporotic. <h3>Methods</h3> Women older than 60 years with osteoporosis were invited to participate in the study. All were able to walk indoor without technical support. Bone density was assessed using a DXA-machine. They were hospitalised for five days in a hospital of rheumatology. A total of 26 subjects were allocated to education only whereas 23 subjects received training by a physiotherapist in addition to education. The education program was provided by a team of professional health workers and had a multifactorial approach to osteoporotic experienced problems. Bodily pain was assessed by SF-36 questionnaire. Follow-up was conducted at 3 and 12 months after intervention. <h3>Results</h3> A multivariate analysis for repeated measurements showed a reduction of bodily pain score of 7.4 (95% CI 2.7–12.1) after 3 month and 9.8 (95% CI 4.2–15.4) after 1 year compared with baseline. There were no significant differences between the groups. <h3>Conclusion</h3> Participation a professional education program reduces the pain experience in women with osteoporosis.
Trustworthiness before Trust — Covid-19 Vaccine Trials and the Black Community
Authors: Rueben C. Warren, Lachlan Forrow, David Augustin Hodge, Robert D. Truog
Journal: New England Journal of Medicine (2020)

Trustworthiness before Trust If Black communities are to participate in Covid-19 trials, clinicians, investigators, and pharmaceutical companies must provide convincing evidence — sufficient to ove...
CXXC5 variant in an immunodeficient patient with a progressive loss of hematopoietic cells
Authors: Hemant R. Joshi, Harry R. Hill, Julie Asch, Rebecca L. Margraf, Emily Coonrod, Jacob Durtschi, Qin Zhou, Xiao He, Karl V. Voelkerding, Attila Kumánovics
Journal: Journal of Allergy and Clinical Immunology (2020)
Fast Recurrent Processing via Ventrolateral Prefrontal Cortex Is Needed by the Primate Ventral Stream for Robust Core Visual Object Recognition
Authors: Kohitij Kar, James J. DiCarlo
Journal: Neuron (2020)

Distributed neural population spiking patterns in macaque inferior temporal (IT) cortex that support core object recognition require additional time to develop for specific, "late-solved" images. This suggests the necessity of recurrent processing in these computations. Which brain circuits are responsible for computing and transmitting these putative recurrent signals to IT? To test whether the ventrolateral prefrontal cortex (vlPFC) is a critical recurrent node in this system, here, we pharmacologically inactivated parts of vlPFC and simultaneously measured IT activity while monkeys performed object discrimination tasks. vlPFC inactivation deteriorated the quality of late-phase (>150 ms from image onset) IT population code and produced commensurate behavioral deficits for late-solved images. Finally, silencing vlPFC caused the monkeys' IT activity and behavior to become more like those produced by feedforward-only ventral stream models. Together with prior work, these results implicate fast recurrent processing through vlPFC as critical to producing behaviorally sufficient object representations in IT.
Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti–PD-1 for patients with anti–PD-1–refractory tumors
Authors: Iván Márquez-Rodas, Federico Longo, Maria E. Rodriguez-Ruiz, Antonio Calles, Santiago Ponce, Maria Jove, Belén Rubio-Viqueira, Jose Luis Perez-Gracia, Ana Gómez-Rueda, Sara López-Tarruella, Mariano Ponz-Sarvise, Rosa Álvarez, Ainara Soria-Rivas, Enrique de Miguel, Rocío Ramos-Medina, Eduardo Castañon, Pablo Gajate, Cayetano Sempere-Ortega, Elisabeth Jiménez-Aguilar, M. Angela Aznar, Aitana Calvo, Pedro P. Lopez-Casas, Salvador Martín-Algarra, Miguel Martín, Dominique Tersago, Marisol Quintero, Ignacio Melero
Journal: Science Translational Medicine (2020)

Intratumoral BO-112 combined with systemic anti–PD-1 shows immunotherapeutic potential to control tumors in patients primarily refractory to anti–PD-1.