tbuckley/cabot-search huggingface dataset:
OP0209 INTERVAL PROLONGATION IN ETANERCEPT-TREATED PATIENTS WITH RHEUMATOID ARTHRITIS, ANKYLOSING SPONDYLITIS OR PSORIATIC ARTHRITIS: AN OPEN-LABEL, RANDOMISED CONTROLLED TRIAL
Authors: M. J. L’ami, J. Ruwaard, E. L. Kneepkens, C. L. M. Krieckaert, M. Nurmohamed, F. Hooijberg, J. C. Van Denderen, A. Van Kuijk, L. Burgemeister, M. Boers, G. J. Wolbink
Journal: Annals of the Rheumatic Diseases (2020)

Background: The majority of patients with a rheumatic disease treated with etanercept may be overexposed. Data regarding etanercept tapering is scarce, particularly in psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Dose reductions can potentially reduce blood drug levels too much, resulting in loss of effect. Objectives: We compared extending the dose interval to continuation of the standard dose and studied the success rate of etanercept discontinuation. Etanercept concentrations were measured throughout the study. Methods: 160 consecutive patients with rheumatoid arthritis (RA), PsA or AS with sustained minimal disease activity (MDA) were enrolled in this 18-month, open-label, randomised controlled trial. The intervention group doubled the dosing-interval at baseline and discontinued etanercept 6 months later. The control group continued the standard dose up to 6 months, after which the dosing-interval was doubled. Primary outcome was the proportion of patients maintaining MDA after 6 months follow-up. Results: At 6 months, MDA status was maintained in 47 (63%) patients in the intervention group and 56 (74%) in the control group (p=0.15), with comparable results in all rheumatic diseases. Median etanercept concentrations decreased from 1.50 µg/mL (25-75 th percentile 1.06-2.65) to 0.46 µg/mL (0.28-0.92) after 6 months of interval prolongation (figure 1). In total, 40% discontinued etanercept successfully with maintained MDA for at least 6 months. Figure 1. Median (with Q1 to Q3 boxplots) etanercept concentrations (per protocol) during the first 6 months of follow-up in the intervention group (prolongation; gray boxplots) and the control group (continuation; white boxplots), separated by disease (RA, PsA, AS). Bars represent 10-90 percentile and outliers are shown separately (dots). Conclusion: As observed in RA, etanercept tapering can be safely attempted in PsA and AS patients in sustained MDA. A substantial proportion of patients could stop etanercept for at least 6 months. In many patients low drug concentrations proved sufficient to control disease activity. However, the risk of minor and major flares is substantial, even in patients continuing standard dosing. References: none Disclosure of Interests: Merel J. l’Ami Speakers bureau: Novartis, Jill Ruwaard: None declared, Eva L. Kneepkens: None declared, Charlotte L.M. Krieckaert: None declared, Michael Nurmohamed Grant/research support from: Not related to this research, Consultant of: Not related to this research, Speakers bureau: Not related to this research, Femke Hooijberg: None declared, J.C. van Denderen: None declared, Arno Van Kuijk: None declared, Lot Burgemeister: None declared, Maarten Boers: None declared, Gert-Jan Wolbink: None declared
A Quantitative Meta-Analysis of the Relation between Occupational Benzene Exposure and Biomarkers of Cytogenetic Damage
Authors: Bernice Scholten, Jelle Vlaanderen, Rob Stierum, Lützen Portengen, Nat Rothman, Qing Lan, Anjoeka Pronk, Roel Vermeulen
Journal: Environmental Health Perspectives (2020)

Background: The genotoxicity of benzene has been investigated in dozens of biomonitoring studies, mainly by studying (classical) chromosomal aberrations (CAs) or micronuclei (MN) as markers of DNA damage. Both have been shown to be predictive of future cancer risk in cohort studies and could, therefore, potentially be used for risk assessment of genotoxicity-mediated cancers. Objectives: We sought to estimate an exposure–response curve (ERC) and quantify between-study heterogeneity using all available quantitative evidence on the cytogenetic effects of benzene exposure on CAs and MN respectively. Methods: We carried out a systematic literature review and summarized all available data of sufficient quality using meta-analyses. We assessed the heterogeneity in slope estimates between studies and conducted additional sensitivity analyses to assess how various study characteristics impacted the estimated ERC. Results: Sixteen CA (1,356 individuals) and 13 MN studies (2,097 individuals) were found to be eligible for inclusion in a meta-analysis. Studies where benzene was the primary genotoxic exposure and that had adequate assessment of both exposure and outcomes were used for the primary analysis. Estimated slope estimates were an increase of 0.27% CA [(95% CI: 0.08%, 0.47%); based on the results from 4 studies] and 0.27% MN [(95% CI: −0.23%, 0.76%); based on the results from 7 studies] per parts-per-million benzene exposure. We observed considerable between-study heterogeneity for both end points (I2&gt;90%). Discussion: Our study provides a systematic, transparent, and quantitative summary of the literature describing the strong association between benzene exposure and accepted markers of genotoxicity in humans. The derived consensus slope can be used as a best estimate of the quantitative relationship between real-life benzene exposure and genetic damage in future risk assessment. We also quantitate the large between-study heterogeneity that exists in this literature, a factor which is crucial for the interpretation of single-study or consensus slopes. https://doi.org/10.1289/EHP6404
A facile and universal method to achieve liposomal remote loading of non-ionizable drugs with outstanding safety profiles and therapeutic effect
Authors: Shuang Zhou, Jinbo Li, Jiang Yu, Liyuan Yang, Xiao Kuang, Zhenjie Wang, Yingli Wang, Hongzhuo Liu, Guimei Lin, Zhonggui He, Dan Liu, Yongjun Wang
Journal: Acta Pharmaceutica Sinica B (2020)

Liposomes have made remarkable achievements as drug delivery vehicles in the clinic. Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs, but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents, thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy. In this study, a series of weak acid drug derivatives were designed by a simplistic one step synthesis, which could be remotely loaded into liposomes by pH gradient method. Cabazitaxel (CTX) weak acid derivatives were selected to evaluate regarding its safety profiles, pharmacodynamics, and pharmacokinetics. CTX weak acid derivative liposomes were superior to Jevtana® in terms of safety profiles, including systemic toxicity, hematological toxicity, and potential central nerve toxicity. Specifically, it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons. Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.
Association Between Topical Calcineurin Inhibitor Use and Keratinocyte Carcinoma Risk Among Adults With Atopic Dermatitis
Authors: Maryam M. Asgari, Ai-Lin Tsai, Lyndsay Avalos, Monica Sokil, Charles P. Quesenberry
Journal: JAMA Dermatology (2020)

Topical calcineurin inhibitors (TCIs), primarily used to treat atopic dermatitis (AD), carry a black box label warning users about the potential for increased skin cancer risk. The risk associated with keratinocyte carcinoma (KC), the most common cancer, defined as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), remains poorly defined because findings from large-scale postmarketing surveillance studies have not been reported.To examine KC risk overall and by subtype (BCC and SCC) among adults with AD exposed to TCIs compared with those exposed to topical corticosteroids (primary comparator group) and those unexposed to TCIs or topical corticosteroids (alternative comparator group) as well as alterations in risk with TCI dose, frequency, and duration of exposure.A retrospective cohort study was conducted at Kaiser Permanente Northern California, a large, integrated health care delivery system, of adults 40 years or older (n = 93 746) with a physician-rendered diagnosis of AD or dermatitis. Patients who were diagnosed from January 1, 2002, to December 31, 2013, were included, with follow-up through December 31, 2017. Data analysis was conducted from June 1, 2016, to October 1, 2018.Time-varying pharmacy-dispensed TCI exposure (n = 7033) over the study period was compared with topical corticosteroids (n = 73 674) and no TCI or topical corticosteroid exposure (n = 46 141).Electronic pathologic testing-validated incident KCs (n = 7744).Among a cohort of 93 746 members, the mean (SD) age was 58.5 (12.7) years, and 55 023 patients (58.7%) were women. Multivariable Cox proportional hazards regression revealed no association between TCI exposure and KC risk (adjusted hazard ratio [aHR], 1.02; 95% CI, 0.93-1.13) compared with topical corticosteroid exposure. Similarly, there were no significant differences in BCC risk (aHR, 1.01; 95% CI, 0.90-1.14, TCI vs topical corticosteroids) or SCC risk (aHR, 0.94; 95% CI, 0.82-1.08, TCI vs topical corticosteroids). Changing the comparator group to unexposed individuals yielded similar findings (aHR, 1.04; 95% CI, 0.91-1.19, TCI vs unexposed for basal cell carcinoma). There were no associations between TCI dose, frequency, and duration of use and BCC, SCC, or overall KC risk.The results of this postmarketing surveillance study of adult health plan members with AD revealed no apparent association between TCI exposure and overall KC, BCC, or SCC risk. Secondary analyses examining dose, frequency, and duration of TCI exposure revealed no associations. These findings suggest that use of TCIs may be safe with respect to KC risk among adults with AD.
What matters emotionally: The importance of pride for cumulative culture
Authors: Jessica L. Tracy
Journal: Behavioral and Brain Sciences (2020)

Abstract Osiurak and Reynaud highlight a major omission of models of cumulative technological culture. I propose an additional problematic omission: pride. By taking this emotion into account, we can address the question of why humans seek to learn, teach, and innovate – three processes essential to cumulative technological culture (CTC). By fostering achievement, prestige, and social learning, pride provides a pivotal piece of the puzzle.
Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
Authors: Sonja C. Schriever, Dhiraj G. Kabra, Katrin Pfuhlmann, Peter Baumann, Emily V. Baumgart, Joachim Nagler, Fabian Seebacher, Luke Harrison, Martin Irmler, Stephanie Kullmann, Felipe Corrêa-da-Silva, Florian Giesert, Ruchi Jain, Hannah Schug, Julien Castel, Sarah Martinez, Moya Wu, Hans-Ulrich Häring, Martin Hrabe de Angelis, Johannes Beckers, Timo D. Müller, Kerstin Stemmer, Wolfgang Wurst, Jan Rozman, Ruben Nogueiras, Meri De Angelis, Jeffery D. Molkentin, Natalie Krahmer, Chun-Xia Yi, Mathias V. Schmidt, Serge Luquet, Martin Heni, Matthias H. Tschöp, Paul T. Pfluger
Journal: Journal of Clinical Investigation (2020)

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron–specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.
Abstract #3275: Up-regulation of Mcl-1 via XBP1-mediated activation of Akt is critical for survival of melanoma cells upon ER stress
Authors: Xu Dong Zhang, Chen Chen Jiang, Rick Thorne, Keryn Lucas, John Allen, Peter Hersey
Journal: Cancer Research (2009)

A number of BH3-only proteins of the Bcl-2 family have been shown to be activated by endoplasmic reticulum (ER) stress and contribute to ER stress-induced apoptosis in various cell types. However, most human melanoma cell lines are insensitive to ER stress-induced cell death, indicating that the apoptosis-inducing potential of BH3-only proteins is inhibited in melanoma cells when submitted to ER stress. We show in this report that up-regulation of the anti-apoptotic Bcl-2 family protein Mcl-1 is critical in protection of melanoma cells upon ER stress by neutralizing the BH3-only proteins PUMA and Noxa. The latter are also up-regulated by ER stress. Inhibition of Mcl-1 by shRNA rendered melanoma cells sensitive to ER stress-induced apoptosis, but the sensitization was partially reversed by siRNA knockdown of PUMA or Noxa. Up-regulation of PUMA and Noxa was mediated by both p53-dependent and -independent transcriptional mechanisms. Similarly, up-regulation of Mcl-1 was also due to increased transcription that was mediated, at least in part, by induction of activation of Akt downstream of the IRE1/XBP1 signaling pathway of the unfolded protein response (UPR). Taken together, these results reveal the mechanisms by which melanoma cells acquire resistance to apoptosis mediated by BH3-only proteins under ER stress, and identify up-regulation of Mcl-1 as an important adaptive mechanism by which melanoma cells survive ER stress conditions. Therefore, targeting Mcl-1 may improve treatment results of clinically available chemotherapeutic drugs and those in development for clinical use that can induce ER stress in melanoma cells.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3275.
Clinical and Dermoscopic Features of Vulvar Melanosis Over the Last 20 Years
Authors: Vincenzo De Giorgi, Alessia Gori, Lorenzo Salvati, Federica Scarfì, Pierandrea Maida, Luciana Trane, Flavia Silvestri, Francesca Portelli, Federico Venturi, Piero Covarelli, Daniela Massi
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> Vulvar melanosis is a common pigmentary change that accounts for most pigmented vulvar lesions. It presents as single or multiple asymptomatic macules or patches of varying size and color that may be asymmetric with poorly defined borders. The differential diagnosis of melanocytic lesions includes melanoma, which creates anxiety for patients and the physicians who diagnose the condition and treat the patients. <h3>Objective</h3> To evaluate the clinical and dermoscopic features of vulvar melanosis and their changes over time. <h3>Design, Setting, and Participants</h3> In this cohort study, patients with vulvar melanosis were recruited and followed up in the Department of Dermatology, University of Florence, Florence, Italy, between January 1, 1998, and June 30, 2019. Data on patient characteristics and on both the clinical and dermoscopic features of the vulvar lesions were collected. Each lesion was photographed clinically and dermoscopically at initial evaluation and at annual follow-up visits. <h3>Main Outcomes and Measures</h3> The clinical, dermoscopic, and histopathologic features of vulvar melanosis and their changes over time. <h3>Results</h3> This cohort study included 129 women (mean age at diagnosis, 46 years [range, 19-83 years]) with vulvar melanosis. A total of 87 patients (67%) with vulvar melanotic lesions were premenopausal, and 84 patients (65%) had received some type of hormone therapy. The most frequent location for vulvar melanosis was the labia minora (55 [43%]), followed by the labia majora (33 [26%]). In 39 of 129 cases (30%), the lesions increased in size and changed color after initial evaluation but ultimately stabilized. No malignant evolution was documented in any patient during a median follow-up of 13 years (range, 5-20 years). <h3>Conclusions and Relevance</h3> This study suggests that vulvar melanosis was a benign entity, and changes in lesions over time did not signify malignant transformation. An association between hormonal status and vulvar melanosis may be hypothesized.
Normalization of Fecal Calprotectin Within 12 Months of Diagnosis Is Associated With Reduced Risk of Disease Progression in Patients With Crohn’s Disease
Authors: Nikolas Plevris, James Fulforth, Mathew Lyons, Spyros I. Siakavellas, Philip W. Jenkinson, Cher S. Chuah, Laura Lucaciu, Rebecca J. Pattenden, Ian D. Arnott, Gareth-Rhys Jones, Charlie W. Lees
Journal: Clinical Gastroenterology and Hepatology (2020)
Genome‐wide Association Study and Meta‐analysis on Alcohol‐Associated Liver Cirrhosis Identifies Genetic Risk Factors
Authors: Tae‐Hwi Schwantes‐An, Rebecca Darlay, Philippe Mathurin, Steven Masson, Suthat Liangpunsakul, Sebastian Mueller, Guruprasad P. Aithal, Florian Eyer, Dermot Gleeson, Andrew Thompson, Beat Muellhaupt, Felix Stickel, Michael Soyka, David Goldman, Tiebing Liang, Lawrence Lumeng, Munir Pirmohamed, Bertrand Nalpas, Jean‐Marc Jacquet, Romain Moirand, Pierre Nahon, Sylvie Naveau, Pascal Perney, Greg Botwin, Paul S. Haber, Helmut K. Seitz, Christopher P. Day, Tatiana M. Foroud, Ann K. Daly, Heather J. Cordell, John B. Whitfield, Timothy R. Morgan, Devanshi Seth
Journal: Hepatology (2020)

Background and Aims Only a minority of heavy drinkers progress to alcohol‐associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and Results We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy‐drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome‐wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta‐analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome‐wide significant risk association of rs738409 in patatin‐like phospholipase domain containing 3 ( PNPLA3 ) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10 −17 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10 −10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas‐associated factor family member 2 ( FAF2 ) (OR = 0.61 [del(T) allele], P = 2.56 × 10 −8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta‐analysis (without conditioning) confirmed genome‐wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13 . Two other previously known loci ( SERPINA1 and SUGP1/TM6SF2 ) were also genome‐wide significant in the meta‐analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
K-12 Virtual Schooling, COVID-19, and Student Success
Authors: Erik Black, Richard Ferdig, Lindsay A. Thompson
Journal: JAMA Pediatrics (2020)

Katherine A. Auger, MD, MSc; Samir S. Shah, MD, MSCE; Troy Richardson, PhD; David Hartley, PhD, MPH; Matthew Hall, PhD; Amanda Warniment, MD; Kristen Timmons, MS; Dianna Bosse, BA; Sarah A. Ferris, BA; Patrick W. Brady, MD, MSc; Amanda C. Schondelmeyer, MD, MSc; Joanna E. Thomson, MD, MPH
Abstract A77: Targeting lymphocyte exclusion in metastatic osteosarcoma
Authors: Laurie Sorenson, Troy A. McEachron
Journal: Cancer Research (2020)

Abstract Osteosarcoma (OS) is the most common bone tumor in pediatric and adolescent/young adult patients. Over the past three decades, significant improvements in the survival rates or therapeutic approaches for these patients have not been made, especially in the context of metastatic disease. While immune checkpoint blockade has revolutionized the therapeutic landscape in various adult malignancies, its impact in OS has been largely underwhelming. Currently, it is unknown whether the lack of therapeutic benefit of immune checkpoint inhibition observed in patients with OS is truly due to treatment inefficacy rather than a limited understanding of the tumor microenvironment that supports this aggressive disease. To address this knowledge gap, we have performed targeted gene expression profiling of metastatic and nonmetastatic osteosarcoma specimens. Our data demonstrate that T cells are largely excluded from the metastatic specimens and that this exclusion significantly correlates with markers of vascular instability. In a pathologic setting, such as that of cancer, VEGF and ANG2 signaling promote vascular instability, which limits leukocyte extravasation and subsequent tumor infiltration. Our data suggest that vascular destabilization mediated by VEGF/ANG2 signaling impedes T-cell infiltration specifically in metastatic OS and identify these molecules as potential targets for therapeutic intervention. Citation Format: Laurie Sorenson, Troy A. McEachron. Targeting lymphocyte exclusion in metastatic osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A77.
The blind men and the elephant: What is missing cognitively in the study of cumulative technological evolution
Authors: Bernard J Crespi
Journal: Behavioral and Brain Sciences (2020)

Abstract I describe and explain (1) evidence regarding a key role for autism spectrum cognition in human technology; (2) tradeoffs of autistic cognition with social skills; and (3) a model of how cumulative technological culture evolves. This model involves positive feedback whereby increased technical complexity selects for enhanced social learning of mechanistic concepts and skills, leading to further advances in technology.
Abstract 13768: Impact of Socioeconomic Status on 30-Day Readmission Risk in Young Patients With First Acute Myocardial Infarction: A Population-Based Cohort Study
Authors: Mohamed M Gad, Anas M Saad, Keerat Rai Ahuja, Najdat Bazarbashi, Antonette Karrthik, Manpreet Kaur, Simrat Kaur, Yasser Sammour, Johnny Chahine, Amer Kadri, Samir R kapadia
Journal: Circulation (2019)

Introduction: Socioeconomic status (SES) has been correlated with cardiovascular disease and myocardial infarctions in numerous studies. Aim: We aim to understand the relationship between SES and t...