tbuckley/cabot-search huggingface dataset:
Identification of small peptides and glycinamide that inhibit melanin synthesis using a positional scanning synthetic peptide combinatorial library
Authors: J. H. Kim, J. K. Seok, Y. M. Kim, Y. C. Boo
Journal: British Journal of Dermatology (2019)

Antimelanogenic peptides are potentially useful to treat hyperpigmentation, but many peptides have limited application because of high cost and/or low activity. To identify small and potent peptide inhibitors of cellular melanin synthesis that are useful for cosmetic and medical applications. A positional scanning synthetic tetrapeptide combinatorial library was used for screening of potentially active peptides. Antimelanogenic activities of the peptide pools and individual peptides were evaluated in B16‐F10 melanoma cells and human epidermal melanocytes treated with alpha‐melanocyte‐stimulating hormone (α‐MSH). Predicted active tetrapeptide sequences were R‐(F/L)‐(C/W)‐(G/R)‐NH2. Of the individual tetrapeptides tested, D3 (RFWG‐NH2) and D5 (RLWG‐NH2) exhibited high antimelanogenic activities. Tetrapeptide D9 (FRWG‐NH2) with a sequence identical to that of a portion of α‐MSH also showed antimelanogenic activity. Of the tripeptides tested, E5 (FWG‐NH2), E6 (LWG‐NH2) and E7 (RWG‐NH2) were relatively more active. Dipeptide F1 (WG‐NH2) and monopeptide G1 (G‐NH2, glycinamide) retained activity, but G2 (Ac‐G‐NH2) and G3 (glycine) did not. The antimelanogenic activities of peptides D3, E5, F1 and G1 were verified in α‐MSH‐stimulated human epidermal melanocytes. Commercially available G‐NH2·HCl suppressed the phosphorylation levels of cAMP‐responsive element binding protein, protein levels of microphthalmia‐associated transcription factor and tyrosinase, l‐tyrosine hydroxylase activity of tyrosinase, and the melanin levels in stimulated cells. Small peptides, including glycinamide and tryptophanyl glycinamide, are potent antimelanogenic agents with potential value for the treatment of skin hyperpigmentation.
Identification of biologic agents to neutralize the bicomponent leukocidins of <i>Staphylococcus aureus</i>
Authors: Rita Chan, Peter T. Buckley, Aidan O’Malley, William E. Sause, Francis Alonzo, Ashira Lubkin, Kristina M. Boguslawski, Angela Payne, Jeffrey Fernandez, William R. Strohl, Brian Whitaker, Anthony Simon Lynch, Victor J. Torres
Journal: Science Translational Medicine (2019)

A key aspect underlying the severity of infections caused by Staphylococcus aureus is the abundance of virulence factors that the pathogen uses to thwart critical components of the human immune response. One such mechanism involves the destruction of host immune cells by cytolytic toxins secreted by S. aureus, including five bicomponent leukocidins: PVL, HlgAB, HlgCB, LukED, and LukAB. Purified leukocidins can lyse immune cells ex vivo, and systemic injections of purified LukED or HlgAB can acutely kill mice. Here, we describe the generation and characterization of centyrins that bind S. aureus leukocidins with high affinity and protect primary human immune cells from toxin-mediated cytolysis. Centyrins are small protein scaffolds derived from the fibronectin type III-binding domain of the human protein tenascin-C. Although centyrins are potent in tissue culture assays, their short serum half-lives limit their efficacies in vivo. By extending the serum half-lives of centyrins through their fusion to an albumin-binding consensus domain, we demonstrate the in vivo efficacy of these biologics in a murine intoxication model and in models of both prophylactic and therapeutic treatment of live S. aureus systemic infections. These biologics that target S. aureus virulence factors have potential for treating and preventing serious staphylococcal infections.
Abstract P033: Estimating the Impact of Risk Factors for Hypertrophic Cardiomyopathy-related Mortality Among Persons Aged 12-35: United States, 1999-2013
Authors: Olubadewa A Fatunde, Matthew D Ritchey
Journal: Circulation (2016)

Background: Hypertrophic cardiomyopathy (HCM), with an estimated prevalence of 1 in 500, is hereditary and often remains asymptomatic and undiagnosed. Although potentially treatable, HCM is a leading cause of sudden cardiac death among adolescents and young adults. While previous HCM-related mortality estimates were extrapolated from cohort studies, this study applies two definitions to death certificate data to estimate national mortality rates and identify at-risk groups. Methods: Death certificates of 12-35 year olds with HCM-related deaths in 1999-2013 were obtained from the National Vital Statistics System. Two definitions were applied: 1) specific—underlying-cause-of-death (UCD) ICD-10 code for HCM (I42.1, I42.2); and 2) sensitive—deaths that met the specific definition; had a UCD code for cardiomyopathy, unspecified (I42.9); or had a contributing cause code of I42.1, I42.2, or I42.9 and a HCM-related UCD (Figure). Deaths with external injury (V01-Y89) or congenital (Q00-Q99) codes were excluded. Ratios comparing rates by age (12-19, 20-35), gender (male, female), time (1999-2003, 2004-2008, 2009-2013), and race (non-Hispanic (NH) white, NH black) were calculated. Results: During 1999-2013, 2,735 specific and 8,390 sensitive HCM-related deaths occurred among 12-35 year olds. Mortality rates were 1.84 and 5.64 per million, respectively. Mortality rates were higher in 20-35 vs 12-19 year olds (specific mortality ratio 1.69, sensitive mortality ratio 5.66); males vs females (5.09, 2.55), and NH blacks vs NH whites (2.66, 3.24), and decreased over time (Figure). Discussion: The HCM-related mortality estimates and at-risk groups (e.g. males, blacks) described here are consistent with findings from previous studies. HCM-related deaths are potentially avoidable through implementation of screening and treatment interventions; however, ideal screening parameters have not been identified. Ongoing surveillance can inform screening improvement efforts and assess for continued rate decreases.
Somatic Mutations in Therapy-Related Myeloid Neoplasms Are Influenced By Therapeutic Modality and Clonal Hematopoiesis of Indeterminate Potential
Authors: Teodora Kuzmanovic, Bhumika J. Patel, Srinivasa Reddy Sanikommu, Yasunobu Nagata, Hassan Awada, Cassandra M. Hirsch, Bartlomiej P. Przychodzen, Remco J Molenaar, Babal K. Jha, Sudipto Mukherjee, Anjali S. Advani, Aziz Nazha, Aaron T. Gerds, Hetty E. Carraway, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Tomas Radivoyevitch
Journal: Blood (2018)
Abstract 20198: Inhaled Hydrogen Gas During DHCA Diminishes Neurologic Injury in Swine
Authors: Alexis Cole, Ali Raza, Arthur Nedder, Patricia E Grant, Hart G Lidov, John E Mayer, John N Kheir
Journal: Circulation (2017)

Introduction: Evidence of ischemia-reperfusion injury (IRI) is common in neonates following surgery for congenital heart disease. Inhaled hydrogen gas may mitigate this injury by selectively reduci...
Twenty-Five Years Diagnosing Gaucher’s Disease in Spain, What We Have Learned?
Authors: Marcio M Andrade-Campos, Jose L Capablo, Jesus J Fraile, Mercedes Roca-Espiau, Pilar Irun, Jorge J Cebolla, Laura Lopez de Frutos, Izaskun Arenaz, Jesus Villarrubia, Abelardo Barez, Horacio Cano, Teresa Molero, Lucia Villalon, Pilar Giraldo
Journal: Blood (2018)
FRI0125 Quantification of tumour necrosis factor in ankylosing spondylitis patients during adalimumab treatment
Authors: L. Berkhout, J. Ruwaard, M.J. l’Ami, G. Wolbink, T. Rispens
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Tumour necrosis factor- (TNF) inhibitors, including adalimumab, are widely used in the treatment of inflammatory autoimmune diseases. Longitudinal (drug-bound) TNF levels in rheumatoid arthritis (RA) patients increased upon adalimumab treatment, and remained stable over two years follow-up. Low TNF levels at week four were associated with a significantly higher frequency of anti-drug antibodies (ADAs) at subsequent time points, significantly less methotrexate (MTX) use at baseline and a significantly reduced clinical response after 52 weeks (unpublished data). <h3>Objectives</h3> To investigate TNF levels during adalimumab treatment in ankylosing spondylitis (AS) patients and to compare this with TNF levels measured in RA patients. <h3>Methods</h3> Longitudinal TNF levels were quantified in 76 consecutive AS patients during adalimumab treatment, using a competition enzyme-linked immunosorbent assay (ELISA). This ELISA is drug-tolerant, which enables the quantification of TNF in the presence of large amounts of TNF-inhibitor. The relationship between TNF levels, drug levels and ADA detection was evaluated. <h3>Results</h3> At baseline, TNF levels were close to the detection limit, but levels increased during adalimumab treatment (figure <b>1A</b>; stratified to concomitant MTX use; black lines represent median TNF (IQR)). The increase in TNF was more gradual in patients treated with adalimumab monotherapy, compared to the increase in TNF levels in patients concomitantly treated with MTX (only 9% of the patients). Similar results were found for adalimumab-treated RA patients, stratified to concomitant MTX use (figure <b>1B</b>; Black lines show median (IQR)). Furthermore, at week four, low TNF levels in AS patients tended to associate with a higher frequency of ADAs after 24 weeks. <h3>Conclusions</h3> This is the first study describing an increase in TNF levels in AS patients during one year of adalimumab treatment. The dynamics in TNF levels is different for patients concomitantly treated with MTX, compared to patients treated with adalimumab monotherapy. Low TNF levels at week four tended to associate with a higher frequency of ADAs, which is potentially associated with the low frequency of MTX use at baseline. <h3>Disclosure of Interest</h3> L. Berkhout: None declared, J. Ruwaard: None declared, M. l'Ami: None declared, G. Wolbink Grant/research support from: Pfizer, Speakers bureau: Pfizer, UCB, AbbVie, Biogen, BMS, T. Rispens Grant/research support from: Genmab, Speakers bureau: Pfizer, AbbVie, Regeneron
AB0846 Personalising care: using infliximab drug trough and anti-drug antibody levels improves clinical treatment decisions and is a cost effective strategy in spondyloarthritis
Authors: S. Dubash, D. Bryer, J. Fitton, A. Barr, C. Vandevelde, H. Marzo-Ortega, J. Freeston
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Personalised medicine tailors treatment to the individual's needs. The advent of biosimilars has led to therapy re-appraisals driven by healthcare commissioning bodies9 demand forcost-effective interventions. Yet, biologic drug dosing is standardised and little is known about the rationale and efficacy of dose adjustment. <h3>Objectives</h3> As part of a service evaluation exercise, we measured serum drug trough levels (DLs) and anti-drug antibodies(ADAbs) in our cohort of patients with axial spondyloarthritis (axSpA) and Psoriatic arthritis (PsA) receiving bio-originator infliximab with the aims of a) informing our decision making upon switching to a biosimilar and b) assessing the impact of this approach to our clinical practice. <h3>Methods</h3> Eligible subjects identified, were counselled and consented by an experienced specialist nurse on DLs and ADAb testing and possible associated outcomes including change in drug class, dose, infusion time interval and switching from bio-originator infliximab to the biosimilar infliximab CT-P13. A treatment algorithm was developed to guide the treating physician. Clinical and outcome data were recorded as per routine practice including disease status, DLs and ADAb titre, and clinical outcome. <h3>Results</h3> We identified 53 subjects. Based upon disease activity, DL and ADAb level, bio-originator infliximab was discontinued in 3 (6%) subjects, the infusion interval was extended in 8 (15%), shortened in 3 (6%), and the dose reduced in 3 (6%) subjects. Four patients (8%) changed to an alternative biologic due to persistent high disease activity on infliximab. ADAbs were absent in 20/28 (71%) subjects on concomitant methotrexate (MTX). Very high titre ADAbs were identified in 8 (15%) subjects with corresponding very low (n=2) or undetectable (n=6) DLs suggesting likely drug-neutralisation. The total estimated cost-savings from drug discontinuation and interval extension or dose reduction were £28,689 per annum in addition to the biosimilar switch saving of £41,184 per annum. <h3>Conclusions</h3> These data from a small cohort suggest that measuring ADAbs and DLs to characterise treatment response, tailor treatment regime and inform biosimilar switching is a clinically efficacious and cost-effective strategy in infliximab-treated SpA patients. We anticipate further significant savings with our cohort receiving subcutaneous therapies. This approach unlocks the potential of "personalised medicine" which supports individualised treatment and brings significant savings to the healthcare provider. <h3>Disclosure of Interest</h3> None declared
Congenital Aspirin-like Defect As a Result of Autosomal Recessive Variants in PTGS1
Authors: Suthesh Sivapalaratnam, Hayman Melissa, Claire Lentaigne, Melissa Chan, Marilena Crescente, Harriet Allan, Katherine Wedderburn, Moghees Hanif, Ernest Turro, Dan P Hart, Kathleen Freson, Kate Downes, NIHR Bioresource, Willem Ouwehand, Michael Laffan, Tim Warner
Journal: Blood (2018)
Calcitriol and taxotere suppress bone metastases in PC-3M-luc-C6 prostate cancer mouse model as monitored by bioluminescence imaging
Authors: Wei-Dong Yu, Yingyu Ma, Rui-Xian Kong, Donald Trump, Candace Johnson
Journal: Cancer Research (2008)

3687  Bone metastasis is the most significant cause of morbidity and mortality in prostate cancer.1,25-dihydroxycholecalciferol (calcitriol) has significant antiproliferative activity in vitro and in vivo in human prostate cancer cells. Taxotere is indicated as a first-line chemotherapy agent for patients with locally advanced or metastatic prostate cancer. We demonstrated that taxotere synergizes with calcitriol in antiproliferative effects as measured by the median dose effect (CI
SP0102 Understanding the language of health services articles
Authors: L. Carmona
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> The only difference of Health services Research with other types of research is the study unit observed. This goes beyond individuals and it may likely refer to doctors, their clinics, or even countries. We still need to work on hypotheses, although some exploratory research can be done; and we always need to start with a research question. If you are unable to find a research question in an original article, remember: stop reading. We will review some of the top questions answered by health services research, such as performance of doctors and services, efficacy of complex interventions, and inequalities. In addition, we will review basic concepts, such as what is an indicator, very frequently used as outcome measures, or what makes a best practice, as well as some special difficulties, such as multilevel (AKA hierarchical) models or instrumental variables. To end, we will review basic concepts in qualitative research, needed to understand the papers dealing with health services research. <h3>Disclosure of Interest</h3> None declared
AB1031 Analysis of mechanism of transient increase in plasma urate levels induced by fructose in rats
Authors: K. Ichida, M. Nagamura, R. Tanino, W. Yoshioka
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Hyperuricemia induces gout and kidney stones and accelerates the progression of renal diseases. Hyperuricemia is a common multifactorial disorder having several environmental factors such as sex, diet, alcohol consumption, and obesity. The increasing prevalence of hyperuricemia in recent years is thought to be due to environmental factors, particularly diet. Based on the reported association between sugar-sweetened beverages and hyperuricemia in epidemiological studies, it has been hypothesised that fructose, the primary sweetener in sugar-sweetened beverages, directly increase plasma urate levels. <h3>Objectives</h3> The aim of this study was to investigate whether and how fructose induces an increase in plasma urate levels. <h3>Methods</h3> Urate in plasma and urine were measured after fructose, glucose, or water was administered to Sprague-Dawley rats at doses of 2.5 or 7.5 g/kg at a time. Intestinal closed loops were made using approximately 10 cm of ileum. Phosphate buffered saline was injected into each intestinal loop. After 4 hours, urate levels in the loops were measured. <h3>Results</h3> Plasma urate level was significantly increased within 15–30 min by oral administration of fructose, without an increase in urinary and intestinal urate excretion, and a decreasing tendency of urate clearance was observed. These actions were evident at a dose of 7.5 g/kg body weight. The absence of an increase in urinary and intestinal urate excretion indicated that an increase in urate production did not result in the increase in plasma urate level. In the meantime, a decrease in urate clearance was suggested to cause the increase in plasma urate level. <h3>Conclusions</h3> The present study demonstrated that oral intake of fructose induces an increase in plasma urate level within a short time and that a decrease in renal urate clearance could mainly work for that. <h3>Disclosure of Interest</h3> None declared
AB0380 Delay in time to diagnosis increases the risk of suffering classic cardiovascular risk factors in patients with rheumatoid arthritis
Authors: M. Robustillo Villarino, A. Sendra García, J.J. Alegre Sancho
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic inflammatory disease that constitutes an independent cardiovascular risk factor (CVRF). In addition, patients with RA have a higher prevalence of CVRF than the general population. <h3>Objectives</h3> To assess whether delay in time to diagnosis of the disease may increase the risk of CVRF in patients with RA. <h3>Methods</h3> Patients diagnosed with RA, according to the EULAR/ACR 2010 classification criteria, were consecutively selected and recruited for a period of 12 months. Delay in time to diagnosis was calculated as the interval between the beginning of first joint symptoms and the diagnosis of RA with start of specific treatment. Furthermore, the presence or absence of arterial hypertension (AHT), dyslipidemia (DL) and diabetes mellitus (DM) were recorded. Whether its diagnosis was prior or subsequent to the diagnosis of the inflammatory disease was also recorded. SPSS version 17.0 software was used for statistical analysis, considering statistical significance for p&lt;0.05. <h3>Results</h3> A total of 244 patients were studied, 73.8% (180) of whom were women and 26.2% (64) men. The mean age was 60.42 years (SD 13.24). Mean Delay in time to diagnosis was 2.1 years (SD 5.5). Mean age at diagnosis was 48.9 years (SD 15.7). Regarding classic CVRF, the percentage of patients with AHT, DL and DM before RA diagnosis were 17.6% (43), 6.1% (15) and 6.1% (15), respectively. After RA diagnosis, 22.5% (55), 43.4% (106) and 3.3% (8) of patients were diagnosed with AHT, DL and DM. Delay in time to diagnosis was significantly associated with AHT, DL and DM diagnosis after RA diagnosis. <h3>Conclusions</h3> A higher inflammatory load, such as that accumulated in RA patients who have delayed the start of treatment, is associated with a higher probability of developing CVRF, which are associated with the appearance of vascular structural damage in the long term. These results are consistent with the effect of inflammatory cytokines on peripheral tissues (increased lipolysis in adipose tissue, increased insulin resistance, increased arterial stiffness). <h3>References</h3> [1] Boyer JF, Gourraud PA, Cantagrel A, Davignon JL, Constantin A. Traditional cardiovascular risk factors in rheumatoid arthritis: A meta-analysis. Joint Bone Spine2011Mar;78:179–83. [2] Dessein PH, Joffe BI, Veller MG, Stevens BA, Tobias M, Reddi K, et al. Traditional and nontraditional cardiovascular risk factors are associated with atherosclerosis in rheumatoid arthritis. J Rheumatol2005Mar;32:435–42. [3] Symmons DPM, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol2011;7:399–408. <h3>Disclosure of Interest</h3> None declared
FRI0053 The changing face of rheumatoid arthritis at the end of the 20th century – a comparative postmortem clinicopathologic study of 237 rheumatoid arthritis patients with aa amyloidosis and systemic vasculitis
Authors: M. Bély, Á. Apáthy
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Most clinicians accept that the course of rheumatoid arthritis (<b>RA</b>) has changed in the last decades. The <b>aim</b> of this study was to verify this clinical impression characterised by systemic vasculitis (<b>SV</b>) and AA amyloidosis (<b>AAa</b>). <h3>Methods</h3> At the National Institute of Rheumatology 12 138 patients died between 1969 and 2000; among them <b>237</b> with <b>RA,</b> who were autopsied. <b>RA</b> was complicated in <b>53 (22.36%)</b> by <b>SV</b>, and in <b>49 (20.68%)</b> of 237 patients by <b>AAa. RA</b> was confirmed clinically according to the criteria of the American College of Rheumatology.<sup>1</sup> The presence of <b>SV</b> and of <b>AAa</b> was determined histologically. The "<b>severity</b>" of vasculitis and the extent of amyloid A deposition/patient was evaluated by semi-quantitative visual estimation on a 0 to 3 plus scale.<sup>2</sup> The average prevalence of <b>SV</b> and <b>AAa</b> was calculated in percentage of the number of <b>RA</b> patients, who died during four periods of time (8–8-8–8 years) covering 32 years (between 1969 and 2000). <h3>Results</h3> During these four periods of time (from 1969 to 2000) the average age of <b>RA</b> patients with <b>SV</b> continuously increased from 57.00 to 68.00 years, and with <b>AAa</b> from 56.71 to 64.08 years. The prevalence of <b>SV</b> and <b>AAa</b> and the proportion of severe cases in% of <b>RA</b> patients are demonstrated on figure 1. <h3>Conclusions</h3> According to our data <b>RA</b> became more aggressive with higher prevalence of <b>SV</b> and <b>AAa</b> at the end of the last century. The longer life spans (longer duration of the immune processes) with repeated exacerbations of vasculitis may have contributed to the increased prevalence of <b>SV</b> at death. The increased prevalence of <b>SV</b> (including fourfold mild and double severe cases) in 32 years supports the changing face of <b>RA</b>. The increased prevalence of <b>AAa</b> may be related to the longer duration of the inflammation as well. The changing trend (inverse proportion) of severe and mild amyloid deposition, i.e. the increase of mild and decrease of severe cases could likely have been related to the introduction of more effective immunosuppressive therapy. The longer disease duration and later death of <b>RA</b> patients with <b>SV</b> or <b>AAa</b> point to more effective therapy. <h3>Reference</h3> [1] Arnett FC, et al. Arthritis Rheum1988;31(3):315–24. PMID: 3358796, doi:10.1002/art.1780310302 [2] Bély M, Apáthy Ágnes: Clinical pathology of rheumatoid arthritis. 1–440 pp.Akadémiai Kiadó, Budapest 2012http://www.akkrt.hu <h3>Disclosure of Interest</h3> None declared
Defining the Molecular Mechanisms through Which the Macrophage Galactose Lectin (MGL) Receptor Regulates Von Willebrand Factor Clearance
Authors: Soracha E Ward, Jamie M O'Sullivan, Sonia Aguila Martinez, Clive Drakeford, Thomas Anthony Jude McKinnon, Alain Chion, James S O'Donnell
Journal: Blood (2018)