tbuckley/cabot-search huggingface dataset:
ST2 expression and release by the bronchial epithelium is downregulated in asthma
Authors: Davinder Kaur, Latifa Chachi, Edith Gomez, Nicolas Sylvius, Shailendra R. Singh, Mohammadali Y. Ramsheh, Ruth Saunders, Christopher E. Brightling
Journal: Allergy (2020)

The airway epithelium plays an important role in wound repair, host defense and is involved in the immunopathogenesis of asthma. Genome wide association studies have described associations between ST2/Interleukin (IL)-33 genes in asthma, but its role in bronchial epithelium is unclear.ST2 expression was examined in subjects with asthma and healthy controls in bronchial epithelium from biopsies (n = 27 versus n = 9) and brushings (n = 34 versus n = 20) by immunohistochemistry and RNA-Seq. In human primary bronchial epithelial cells ST2 mRNA and protein expression were assessed by qPCR, flow cytometry, Western blotting, and immunofluorescence. IL-33 function in epithelial cells was examined by intracellular calcium measurements, wound healing assays, and synthetic activation by gene array and ELISA.Bronchial epithelial ST2 protein expression was significantly decreased in biopsies in subjects with asthma compared to healthy controls (P = .039). IL1RL1 gene expression in bronchial brushes was not different between health and disease. In vitro primary bronchial epithelial cells expressed ST2 and IL-33 stimulation led to an increase in intracellular calcium, altered gene expression, but had no effect upon wound repair. Epithelial cells released sST2 spontaneously, which was reduced following stimulation with TNFα or poly-IC. Stimulation by TNFα or poly-IC did not affect the total ST2 expression by epithelial cell whereas surface ST2 decreased in response to TNFα, but not poly-IC.In asthma, bronchial epithelium protein expression of ST2 is decreased. Our in vitro findings suggest that this decrease might be a consequence of the pro-inflammatory environment in asthma or in response to viral infection.
Outcomes and treatment responses, including work productivity, among people with axial spondyloarthritis living in urban and rural areas: a mixed-methods study within a national register
Authors: Rosemary J Hollick, Kevin Stelfox, Linda E Dean, Joanna Shim, Karen Walker-Bone, Gary J Macfarlane
Journal: Annals of the Rheumatic Diseases (2020)

Objective To examine differences in clinical and patient-reported outcomes, including work, in individuals with axial spondyloarthritis (axSpA) living in rural and urban settings. Methods Using a sequential, explanatory mixed-method design, data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis were used to (1) characterise participants with axSpA living in rural and urban areas and (b) assess any differences in outcome after commencement of biologic therapy (phase 1). Semistructured interviews (phase 2) further explored the results from phase 1. Results Patients with axSpA living in rural areas were older and more likely to work in a physical job. Among patients prescribed biologics, there were no differences in response to biologics, but after adjustment for age, sex and local area deprivation rural dwellers reported more presenteeism and overall work impairment. Work effects could be explained by accounting for individual differences in disease activity, fatigue, physical function and job type. Interviews highlighted the complex relationship between clinical factors, contextual factors (work environment, job demands) and work disability. The ability to work and flexibility in terms of what, when and how tasks are undertaken were important. Support from employers was variable and healthcare professionals were often perceived as unsupportive. Conclusions Patients with axSpA living in rural areas report a greater impact of their disease on work productivity. New measures are needed to capture important contextual factors and comprehensively determine the impact of long-term conditions on work. Future European League Against Rheumatism axSpA recommendations should include support to work as a target to optimise quality of life in patients with axSpA.
Lateral Gene Transfer Acts As an Evolutionary Shortcut to Efficient C4 Biochemistry
Authors: Chatchawal Phansopa, Luke T Dunning, James D Reid, Pascal-Antoine Christin
Journal: Molecular Biology and Evolution (2020)

Abstract The adaptation of proteins for novel functions often requires changes in their kinetics via amino acid replacement. This process can require multiple mutations, and therefore extended periods of selection. The transfer of genes among distinct species might speed up the process, by providing proteins already adapted for the novel function. However, this hypothesis remains untested in multicellular eukaryotes. The grass Alloteropsis is an ideal system to test this hypothesis due to its diversity of genes encoding phosphoenolpyruvate carboxylase, an enzyme that catalyzes one of the key reactions in the C4 pathway. Different accessions of Alloteropsis either use native isoforms relatively recently co-opted from other functions or isoforms that were laterally acquired from distantly related species that evolved the C4 trait much earlier. By comparing the enzyme kinetics, we show that native isoforms with few amino acid replacements have substrate KM values similar to the non-C4 ancestral form, but exhibit marked increases in catalytic efficiency. The co-option of native isoforms was therefore followed by rapid catalytic improvements, which appear to rely on standing genetic variation observed within one species. Native C4 isoforms with more amino acid replacements exhibit additional changes in affinities, suggesting that the initial catalytic improvements are followed by gradual modifications. Finally, laterally acquired genes show both strong increases in catalytic efficiency and important changes in substrate handling. We conclude that the transfer of genes among distant species sharing the same physiological novelty creates an evolutionary shortcut toward more efficient enzymes, effectively accelerating evolution.
The rare finding of a Dieulafoy’s lesion at the major papilla
Authors: Samuel Han, Mihir S. Wagh, Sachin Wani
Journal: Endoscopy (2020)

A 58-year-old man with history of diabetes, hypertension, chronic kidney disease, and chronic calcific pancreatitis presented with five episodes of coffee-ground emesis and melena. The patient had previously required endoscopic transmural drainage of walled-off pancreatic necrosis 1 year earlier with a lumen-apposing metal stent, which had since been removed.
A study comparing the biologic drugs ixekizumab and guselkumab for the treatment of moderate‐to‐severe plaque psoriasis
Authors: A. Blauvelt, K. Papp, A. Gottlieb, A. Jarell, K. Reich, C. Maari, K.B. Gordon, L.K. Ferris, R.G. Langley, Y. Tada, R.G. Lima, H. Elmaraghy, G. Gallo, L. Renda, S.Y. Park, R. Burge, J. Bagel
Journal: British Journal of Dermatology (2020)

Psoriasis is a skin disease that causes red, scaly and itchy patches of skin all over the body. It affects about 125 million people worldwide. As well as causing decreased quality of life, more widespread psoriasis often affects internal health. New drugs developed in the last few years often help people with psoriasis to achieve completely clear skin, and improve overall health. Two of these drugs are ixekizumab (IXE) and guselkumab (GUS). IXE and GUS work in different ways, however, and some prior research showed that IXE may work faster than GUS. In this study, researchers from the U.S.A. and Canada tested these drugs head‐to‐head, measuring speed of clearance and complete skin clearance rates over the first 12 weeks after starting drug. People in this study received either IXE or GUS. After 12 weeks, completely clear skin was achieved by 16% more people if they were treated with IXE compared to GUS (41% of people who took IXE versus 25% of people who took GUS). More people on IXE than GUS had 50% clearer skin after just one week and 75% clearer skin after two weeks. Itching, skin pain, and quality of life also improved faster with IXE compared to GUS. The number of patients with serious side effects was similar for IXE and GUS. Overall, people with psoriasis who take IXE may get clear skin faster and feel better more quickly than people who take GUS. This is a summary of the study: A head‐to‐head comparison of ixekizumab vs. guselkumab in patients with moderate‐to‐severe plaque psoriasis: 12‐week efficacy, safety and speed of response from a randomized, double‐blinded trial
Trends of nanotechnology in type 2 diabetes mellitus treatment
Authors: Yannis V. Simos, Konstantinos Spyrou, Michaela Patila, Niki Karouta, Haralambos Stamatis, Dimitrios Gournis, Evangelia Dounousi, Dimitrios Peschos
Journal: Asian Journal of Pharmaceutical Sciences (2020)

There are several therapeutic approaches in type 2 diabetes mellitus (T2DM). When diet and exercise fail to control hyperglycemia, patients are forced to start therapy with antidiabetic agents. However, these drugs present several drawbacks that can affect the course of treatment. The major disadvantages of current oral modalities for the treatment of T2DM are mainly depicted in the low bioavailability and the immediate release of the drug, generating the need for an increase in frequency of dosing. In conjugation with the manifestation of adverse side effects, patient compliance to therapy is reduced. Over the past few years nanotechnology has found fertile ground in the development of novel delivery modalities that can potentially enhance anti-diabetic regimes efficacy. All efforts have been targeted towards two main vital steps: (a) to protect the drug by encapsulating it into a nano-carrier system and (b) efficiently release the drug in a gradual as well as controllable manner. However, only a limited number of studies published in the literature used
Abstract 12919: Effects of Marine Oil Supplementation on Cytokine and Lipid Mediator Content of HDL in Patients With Peripheral Arterial Disease
Authors: Thomas A Sorrentino, Kate Townsend Creasy, Melinda S Schaller, Brian E Sansbury, Pete Mitchell, Matthew Spite, John P Kane, Michael S Conte
Journal: Circulation (2018)

Introduction: Peripheral arterial disease (PAD) is characterized by chronic inflammation. High-density lipoprotein (HDL) influences vascular inflammation in part by trafficking signals that modulat...
SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation
Authors: Lea Južnić, Kenneth Peuker, Anne Strigli, Mario Brosch, Alexander Herrmann, Robert Häsler, Michael Koch, Liz Matthiesen, Yvonne Zeissig, Britt-Sabina Löscher, Alexander Nuber, Gunnar Schotta, Volker Neumeister, Triantafyllos Chavakis, Thomas Kurth, Mathias Lesche, Andreas Dahl, Anne von Mässenhausen, Andreas Linkermann, Stefan Schreiber, Konrad Aden, Philip C Rosenstiel, Andre Franke, Jochen Hampe, Sebastian Zeissig
Journal: Gut (2020)

Objective The intestinal epithelium is a rapidly renewing tissue which plays central roles in nutrient uptake, barrier function and the prevention of intestinal inflammation. Control of epithelial differentiation is essential to these processes and is dependent on cell type-specific activity of transcription factors which bind to accessible chromatin. Here, we studied the role of SET Domain Bifurcated Histone Lysine Methyltransferase 1, also known as ESET (SETDB1), a histone H3K9 methyltransferase, in intestinal epithelial homeostasis and IBD. Design We investigated mice with constitutive and inducible intestinal epithelial deletion of Setdb1 , studied the expression of SETDB1 in patients with IBD and mouse models of IBD, and investigated the abundance of SETDB1 variants in healthy individuals and patients with IBD. Results Deletion of intestinal epithelial Setdb1 in mice was associated with defects in intestinal epithelial differentiation, barrier disruption, inflammation and mortality. Mechanistic studies showed that loss of SETDB1 leads to de-silencing of endogenous retroviruses, DNA damage and intestinal epithelial cell death. Predicted loss-of-function variants in human SETDB1 were considerably less frequently observed than expected, consistent with a critical role of SETDB1 in human biology. While the vast majority of patients with IBD showed unimpaired mucosal SETDB1 expression, comparison of IBD and non-IBD exomes revealed over-representation of individual rare missense variants in SETDB1 in IBD, some of which are predicted to be associated with loss of function and may contribute to the pathogenesis of intestinal inflammation. Conclusion SETDB1 plays an essential role in intestinal epithelial homeostasis. Future work is required to investigate whether rare variants in SETDB1 contribute to the pathogenesis of IBD.
Association of Electronic Nicotine Delivery System Use With Cigarette Smoking Relapse Among Former Smokers in the United States
Authors: Colm D. Everard, Marushka L. Silveira, Heather L. Kimmel, Daniela Marshall, Carlos Blanco, Wilson M. Compton
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Relapse to smoking among former smokers is a serious clinical concern, and use of electronic nicotine delivery systems (ENDS) has been proposed as a new risk factor for relapse. Understanding the specificity of this risk can help guide clinical practice and lead to improved health outcomes. <h3>Objective</h3> To assess the associations of ENDS use with cigarette smoking relapse among adult former cigarette smokers. <h3>Design, Setting, and Participants</h3> This cohort study examined data from the Population Assessment of Tobacco and Health Study, waves 1 to 4 (2013-2018). Cox proportional hazards models were developed. This is an ongoing, nationally representative, longitudinal cohort study in the US. Participants included adult (≥18 years) former cigarette smokers who reported no tobacco product use at wave 1 (unweighted n = 2273), separated into recent former cigarette smokers (last smoked ≤12 months previously) and long-term former smokers (last smoked &gt;12 months previously). Data analysis was conducted from July to August 2019. <h3>Exposures</h3> Self-reported use of cigarettes, ENDS, and other tobacco products (ie, cigars, pipe tobacco, hookah, snus tobacco, other smokeless tobacco, and dissolvable tobacco) was assessed. <h3>Main Outcomes and Measures</h3> Self-reported current (every day or some days) use of cigarettes at follow-up interviews. <h3>Results</h3> Of 2273 adult former cigarette smokers, 51.8% (95% CI, 49.7%-53.8%) were women, 65.0% (95% CI, 62.6%-67.4%) were older than 50 years, and 79.5% (95% CI, 77.8%-81.2%) were non-Hispanic white participants. Use of ENDS was associated with significant risk of cigarette smoking relapse among recent former smokers (adjusted hazard ratio [AHR], 1.63; 95% CI, 1.04-2.53; unweighted n = 304) and among long-term former smokers (AHR, 3.79; 95% CI, 1.75-8.20; unweighted n = 1554). Use of other tobacco products was also associated with significant risk for cigarette smoking relapse among recent former smokers (AHR, 1.97; 95% CI, 1.27-3.05) and among long-term former smokers (AHR, 3.82; 95% CI, 1.91-7.66). <h3>Conclusions and Relevance</h3> In this study, use of ENDS and other tobacco products was associated with increased risk of cigarette smoking relapse among former cigarette smokers who did not use any tobacco product at wave 1 of the PATH Study. For clinicians treating former smokers who have successfully quit all nicotine products, the implications are that use of ENDS products should be discouraged, just as use of all other tobacco products is discouraged.
A life immersed in science
Authors: Jules Morgan
Journal: The Lancet Rheumatology (2020)

"If you're going through hell, keep going", says Colin Wilkinson, borrowing the sentiment widely attributed to Winston Churchill. It is a fitting mantra for a man managing the reality of living with psoriatic arthritis, osteoporosis, and the consequences of septic arthritis. Churchill's war-time speeches remain timeless in their meaning: overcoming adversity and being the stronger for it. Colin absolutely embodies this spirit.
FRI0583 VALIDATION OF THE MODIFIED FATIGUE IMPACT SCALE IN DANISH PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: C. I. Junker, K. Duch, L. Dreyer, J. W. Gregersen, S. Kristensen
Journal: Annals of the Rheumatic Diseases (2020)

Background: Patients with systemic lupus erythematosus (SLE) experience significant fatigue, a debilitating symptom associated with reduced quality of life. A simple, reliable multidimensional method for assessing fatigue has not yet been validated for Danish patients with SLE. Objectives: The primary objective was to study the internal consistency, test-retest reliability, and construct validity (convergent and discriminant validity) of the multidimensional Modified Fatigue Impact Scale (MFIS) in patients with SLE. The secondary objective was to investigate the contribution of disease activity and organ damage to fatigue. Methods: Data from the ”Bio and Genome Bank Study in Centre for SLE and Vasculitis” obtained through routine visits were used. Fatigue was assessed using the MFIS and Short Form 36 (SF36). Internal consistency of the MFIS was assessed with Cronbach’s alpha (α). Test-retest reliability was evaluated using the intraclass correlation coefficient (ICC). Construct validity was studied using Spearman’s rank correlation coefficient (r s ) and Principal Component Analysis (PCA) between MFIS and SF36 vitality (VT-SF36) and mental health (MH-SF36) subscales. Association between MFIS and disease activity and organ damage was estimated with Spearman’s rank correlation coefficient. Results: The study included 30 patients with SLE. Internal consistency of the MFIS was excellent with Cronbach’s α = 0.97 for the complete scale. Excellent test-retest reliability was found with ICC = 0.95 (95% confidence interval: 0.88-0.98, p &lt; 0.05). Construct validity was confirmed by Spearman’s correlation (VT-SF36: r s = −0.73, p &lt; 0.001 (Fig. 1). MH-SF36: r s = −0.74, p &lt; 0.001 (Fig. 2)) and PCA with explained variance from the first two principal components (PC) (VT-SF36: PC1 = 60.2%, PC2 = 8.5%. MH-SF36: PC1 = 58.5%, PC2 = 7.4%). No significant correlation was found between the MFIS and SLEDAI (r s = 0.04, p = 0.84) or SLICC Damage Index (r s = 0.32, p = 0.08). Figure 1. Scatter plot of the Modified Fatigue Impact Scale (MFIS) and the Short Form 36 vitality (VT-SF36) subscale. Figure 2. Scatter plot of the Modified Fatigue Impact Scale (MFIS) and the Short Form 36 mental health (MH-SF36) subscale. Conclusion: The present study found the multidimensional assessment of fatigue with MFIS to be a reliable and valid instrument in SLE. The MFIS might provide more detailed information about fatigue in future studies. In agreement with some previous studies we found no association between fatigue and SLEDAI or SLICC which raises questions about the cause of this symptom. Further and larger studies are needed to investigate if any association between fatigue and disease components exist. Disclosure of Interests: None declared
Abstract B19: Role of cell-cell communication in endocrine therapy-resistant breast cancer
Authors: Surojeet Sengupta, Rong Hu, Zachary Susswein, Adeola Fagunloye, Shweta Bansal, Robert Clarke
Journal: Cancer Research (2020)

Abstract Endocrine therapy is the mainstay for the treatment of estrogen-receptor positive (ER+) breast cancer. However, frequent emergence of endocrine resistance is a major clinical challenge. Cell-cell cooperation in the tumor microenvironment plays a vital role in acquiring resistance, but its role is poorly understood. We studied the interactions among endocrine-resistant (R) and -sensitive (S) breast cancer cells in the presence and absence of ER-targeted endocrine therapy. We measured changes in admixed cell population remodeling by dual fluorescent labeling of LCC1 (S) with eGFP (green fluorescent protein) and their derived resistant variant (selected against the antiestrogen fulvestrant) LCC9 (R) with mCherry (red fluorescent protein), respectively. Thus, unlike most prior studies, these are genetically related cells, rather than ER+ and ER- cell lines obtained from different patients. Our results revealed that “S”cells (LCC1) acquired the phenotype of “R” cells when cultured in a mixed population. A ratio of 5:1 of S:R cells in mixed population was sufficient to confer resistance to fulvestrant to the S cells within a six-day period. Furthermore, we show that acquirement of this resistant phenotype for the S cells was partially blocked by inhibition of either gap junctions or exosome secretion, suggesting a role of cell-cell contact as well as extracellular vesicles. Global proteomic analysis of pure and admixed S and R cell populations showed that R and S can alter key molecular features of each other when present in mixed cell populations. We used a Bayesian approach to fit single culture cell populations to infer density-dependent growth parameters (growth rate, carrying capacity) and a generalized Lotka-Volterra model to understand how S and R coculture populations may be depressing or supporting growth of the other. Our results identify a net mutualistic interaction between the susceptible and resistant cancer strains, demonstrating that there are ecological dynamics to cancer resistance. In some tumors, ecological dynamics may be more mechanistically relevant than simple Darwinian-based clonal selection in driving tumor heterogeneity and determining response to treatment. Our study strongly indicates that different tumor cell types that may exist in tumors are able to influence each other, which leads to alteration of phenotype. Note: This abstract was not presented at the conference. Citation Format: Surojeet Sengupta, Rong Hu, Zachary Susswein, Adeola Fagunloye, Shweta Bansal, Robert Clarke. Role of cell-cell communication in endocrine therapy-resistant breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B19.