tbuckley/cabot-search huggingface dataset:
Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies
Authors: Andreas Schwarting, Tamara Möckel, Freya Lütgendorf, Konstantinos Triantafyllias, Sophia Grella, Simone Boedecker, Arndt Weinmann, Myriam Meineck, Clemens Sommer, Ingrid Schermuly, Andreas Fellgiebel, Felix Luessi, Julia Weinmann-Menke
Journal: Annals of the Rheumatic Diseases (2019)

Objectives We explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE). Methods Serum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuronal cell lines. Treatment effects were studied in 86 patients with lupus under belimumab therapy. Results We found a close correlation between the titre of anti-NR2 antibodies, the severity of fatigue, the clinical disease activity index (Systemic Lupus Erythematosus Disease Activity Index 2000) and anti-double stranded DNA antibodies—independently of the presence of neuropsychiatric lupus manifestations. Pathogenic effects could be demonstrated by (1) detection of anti-NR2 antibodies in the cerebrospinal fluid, (2) in situ binding of anti-NR2 antibodies to NMDAR of the hippocampus area and (3) distinct functional effects in vitro: downregulating the energy metabolism of neuronal cells without enhanced cytotoxicity. Treatment with belimumab for at least 6 months affected both the severity of fatigue and the levels of anti-NR2 antibodies. Conclusion The presence of anti-NR2 antibodies in patients with SLE with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with SLE.
AB0211 NEUTROPHIL-DERIVED EXOSOME S100A8/A9 INHIBITS ANGIOGENESIS IN SYSTEMIC SCLEROSIS
Authors: LI Liya, Zuo Xiaoxia, Xiao Yizhi, DI Liu, Luo Hui, Zhu Honglin
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, inflammation, and extensive fibrosis of the skin and organs. Exosomes (EXOs) are cell-derived vesicles 30-150 nm in size that contain various mRNAs, microRNAs and proteins. <h3>Objectives</h3> Here, we aimed to investigate the roles of EXOs in SSc pathogenesis, especially in angiogenesis. <h3>Methods</h3> EXOs were respectively isolated from plasma, cultured peripheral blood mononuclear cells (PBMCs) and neutrophil supernatants, and were identified by transmission electron microscopy. The expression of S100A8/A9 was measured by real-time PCR and ELISA. Proliferation, migration and scratch assays in human dermal microvascular endothelial cells (HDMECs) were used to study the influence of neutrophil EXOs and neutrophil EXOs S100A8/A9. We also performed a genome-wide transcriptome analysis on PBMCs from 19 SSc patients and 18 matched normal controls (NC) using Illumina BeadChip arrays. The ingenuity pathway analysis (IPA) tool and Database for Annotation, Visualization and Integrated Discovery (DAVID) were used for bioinformatics analysis. <h3>Results</h3> Plasma EXOs and neutrophil EXOs from SSc patients suppressed the proliferation and migration of HDMECs. Using a microarray analysis we found 28% genes upregulated in PBMCs could exist in EXOs, especially the S100 protein family, including S100A8/A9. High levels of S100A8/A9 were consistently verified in SSc plasma, PBMCs, plasma EXOs, PBMC EXOs and neutrophil EXOs. Particularly, S100A8/A9 expression in neutrophil EXOs was distinctly higher than that in PBMC EXOs in SSc patients. Furthermore, we found that neutrophil EXOs S100A8/A9 inhibit the proliferation and migration of HDMECs, and that might through Toll-like receptor 4 (TLR4) pathway. <h3>Conclusion</h3> S100A8/A9 is one of components of neutrophil EXOs that regulates vascular endothelial cell angiogenesis in SSc patients, most likely by activating the TLR4 signalling pathway. <h3>Acknowledgement</h3> This study was funded by grants from the National Key Research and Development Program of China (2016YFC0903900), National Natural Science Foundation of China (81671622), Hunan Provincial Natural Science Foundation (2018JJ3823), Clinical Research Fund of Xiangya Hospital Central South University (2014L10) and Independent Innovation Projects of Central South University (2018zzst290). <h3>Disclosure of Interests</h3> None declared
Degenerative Expansion of a Young Supergene
Authors: Eckart Stolle, Rodrigo Pracana, Philip Howard, Carolina I Paris, Susan J Brown, Claudia Castillo-Carrillo, Stephen J Rossiter, Yannick Wurm
Journal: Molecular Biology and Evolution (2018)

Long-term suppression of recombination ultimately leads to gene loss, as demonstrated by the depauperate Y and W chromosomes of long-established pairs of XY and ZW chromosomes. The young social supergene of the Solenopsis invicta red fire ant provides a powerful system to examine the effects of suppressed recombination over a shorter timescale. The two variants of this supergene are carried by a pair of heteromorphic chromosomes, referred to as the social B and social b (SB and Sb) chromosomes. The Sb variant of this supergene changes colony social organization and has an inheritance pattern similar to a Y or W chromosome because it is unable to recombine. We used high-resolution optical mapping, k-mer distribution analysis, and quantification of repetitive elements on haploid ants carrying alternate variants of this young supergene region. We find that instead of shrinking, the Sb variant of the supergene has increased in length by more than 30%. Surprisingly, only a portion of this length increase is due to consistent increases in the frequency of particular classes of repetitive elements. Instead, haplotypes of this supergene variant differ dramatically in the amounts of other repetitive elements, indicating that the accumulation of repetitive elements is a heterogeneous and dynamic process. This is the first comprehensive demonstration of degenerative expansion in an animal and shows that it occurs through nonlinear processes during the early evolution of a region of suppressed recombination.
Overdiagnosis and Lives Saved by Reflex Testing Men With Intermediate Prostate-Specific Antigen Levels
Authors: Roman Gulati, Todd M Morgan, Teresa A'mar, Sarah P Psutka, Jeffrey J Tosoian, Ruth Etzioni
Journal: JNCI Journal of the National Cancer Institute (2019)

Several prostate cancer (PCa) early-detection biomarkers are available for reflex testing in men with intermediate prostate-specific antigen (PSA) levels. Studies of these biomarkers typically provide information about diagnostic performance but not about overdiagnosis and lives saved, the primary drivers of associated harm and benefit.We projected overdiagnoses and lives saved using an established microsimulation model of PCa incidence and mortality with screening and treatment efficacy based on randomized trials. We used this framework to evaluate four urinary reflex biomarkers (measured in 1112 men presenting for prostate biopsy at 10 US academic or community clinics) and two hypothetical ideal biomarkers (with 100% sensitivity or specificity for any or for high-grade PCa) at one-time screening tests at ages 55 and 65 years.Compared with biopsying all men with elevated PSA, reflex testing reduced overdiagnoses (range across ages and biomarkers = 8.8-60.6%) but also reduced lives saved (by 7.3-64.9%), producing similar overdiagnoses per life saved. The ideal biomarker for high-grade disease improved this ratio (by 35.2% at age 55 years and 42.0% at age 65 years). Results were similar under continued screening for men not diagnosed at age 55 years, but the ideal biomarker for high-grade disease produced smaller incremental improvement.Modeling is a useful tool for projecting the implications of using reflex biomarkers for long-term PCa outcomes. Under simplified conditions, reflex testing with urinary biomarkers is expected to reduce overdiagnoses but also produce commensurate reductions in lives saved. Reflex testing that accurately identifies high-grade PCa could improve the net benefit of screening.
Reverse gene–environment interaction approach to identify variants influencing body-mass index in humans
Authors: Kristina M. Garske, David Z. Pan, Zong Miao, Yash V. Bhagat, Caroline Comenho, Christopher R. Robles, Jihane N. Benhammou, Marcus Alvarez, Arthur Ko, Chun Jimmie Ye, Joseph R. Pisegna, Karen L. Mohlke, Janet S. Sinsheimer, Markku Laakso, Päivi Pajukanta
Journal: Nature Metabolism (2019)
Time-resolved dual RNA-seq reveals extensive rewiring of lung epithelial and pneumococcal transcriptomes during early infection
Authors: Rieza Aprianto, Jelle Slager, Siger Holsappel, Jan-Willem Veening
Journal: Genome biology (2016)

Streptococcus pneumoniae, the pneumococcus, is the main etiological agent of pneumonia. Pneumococcal infection is initiated by bacterial adherence to lung epithelial cells. The exact transcriptional changes occurring in both host and microbe during infection are unknown. Here, we developed a time-resolved infection model of human lung alveolar epithelial cells by S. pneumoniae and assess the resulting transcriptome changes in both organisms simultaneously by using dual RNA-seq.Functional analysis of the time-resolved dual RNA-seq data identifies several features of pneumococcal infection. For instance, we show that the glutathione-dependent reactive oxygen detoxification pathway in epithelial cells is activated by reactive oxygen species produced by S. pneumoniae. Addition of the antioxidant resveratrol during infection abates this response. At the same time, pneumococci activate the competence regulon during co-incubation with lung epithelial cells. By comparing transcriptional changes between wild-type encapsulated and mutant unencapsulated pneumococci, we demonstrate that adherent pneumococci, but not free-floating bacteria, repress innate immune responses in epithelial cells including expression of the chemokine IL-8 and the production of antimicrobial peptides. We also show that pneumococci activate several sugar transporters in response to adherence to epithelial cells and demonstrate that this activation depends on host-derived mucins.We provide a dual-transcriptomics overview of early pneumococcal infection in a time-resolved manner, providing new insights into host-microbe interactions. To allow easy access to the data by the community, a web-based platform was developed ( http://dualrnaseq.molgenrug.nl ). Further database exploration may expand our understanding of epithelial-pneumococcal interaction, leading to novel antimicrobial strategies.
Comprehensive Clinical and Genetic Characterization of Hyperprogression Based on Volumetry in Advanced Non–Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitor
Authors: Youjin Kim, Chu Hyun Kim, Ho Yun Lee, Se-Hoon Lee, Hong Sook Kim, Sook Lee, Hongui Cha, Sungjun Hong, Kyunga Kim, Sang Won Seo, Jong-Mu Sun, Myung-Ju Ahn, Jin Seok Ahn, Keunchil Park
Journal: Journal of Thoracic Oncology (2019)
Blocking interleukin-6 trans-signaling protects against renal fibrosis by suppressing STAT3 activation
Authors: Wei Chen, Hui Yuan, Wenmin Cao, Tianwei Wang, Wei Chen, Hang Yu, Yao Fu, Bo Jiang, Hong Zhou, Hongqian Guo, Xiaozhi Zhao
Journal: Theranostics (2019)

Rationale: Renal fibrosis is the terminal manifestation of chronic and irreversible renal disease.Effective therapies other than dialysis are extremely limited.In this study, we investigated the potential effects of targeting elevated interleukin-6 (IL-6) levels in the treatment of renal fibrosis.Methods: Fc-gp130 was used to specifically block IL-6 trans-signaling.Unilateral ureteral occlusion (UUO) and ischemia reperfusion (IR) mouse models were constructed to investigate the therapeutic effect of Fc-gp130 on renal fibrosis.The role of IL-6 trans-signaling and phosphorylation of signal transducer and activator of transcription (STAT) 3 in regulating fibroblast accumulation and extracellular matrix protein deposition were evaluated in cell experiments and mouse models. Results:The kidneys of mice with UUO were found to have elevated soluble IL-6 receptor (sIL-6R) levels in the progression of fibrosis.Fc-gp130 attenuated renal fibrosis in mice, as evidenced by reductions in tubular atrophy and the production of extracellular matrix protein.Blockade of IL-6 trans-signaling with Fc-gp130 also reduced inflammation levels, immune cell infiltration, and profibrotic cytokines expression in renal tissue, with decreased STAT3 phosphorylation and reduced fibroblast accumulation in the renal tissue.In vitro, Fc-gp130 also reduced the phosphorylation of STAT3 induced by transforming growth factor (TGF)-β1 in fibroblasts.Furthermore, the therapeutic effect of Fc-gp130 was confirmed in a model of acute kidney injury-chronic kidney disease.Conclusion: Overall, IL-6 trans-signaling may contribute to crucial events in the development of renal fibrosis, and the targeting of IL-6 trans-signaling by Fc-gp130 may provide a novel therapeutic strategy for the treatment of renal fibrosis.
Abstract 15916: Improvement of Cardiac Function with Increasing Stimulus Strength during Left Ventricular Pacing in Cardiac Resynchronization Therapy
Authors: Kohei Ishibashi, Takashi Kubo, Takashi Tanimoto, Takashi Yamano, Yasushi Ino, Tomoyuki Yamaguchi, Kumiko Hirata, Toshio Imanishi, Takashi Akasaka
Journal: Circulation (2012)

Introduction. Cardiac resynchronization therapy (CRT) has become an established option for reducing the risk of mortality as well as improving symptoms in patients with severe heart failure. Howeve...
AB1267 THE PREVALENCE OF RHUPUS SYNDROME IN A MONOCENTRIC TERTIARY REFERRAL COHORT
Authors: Silvia Grazietta Foddai, Elena Rubini, Massimo Radin, Irene Cecchi, Daniela Rossi, Savino Sciascia, Dario Roccatello
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two systemic chronic autoimmune diseases characterised by a wide spectrum of clinical and immune-pathological features. In clinical practice, the concept of <i>Overlap Syndrome</i> is defined when the two diseases coexist in the same patient. Rhupus syndrome is a rare clinical condition, characterized by overlap of SLE and RA. However, it is still subject to debate whether the syndrome should be considered a distinctive entity or an aggressive form of SLE. To date, the estimated prevalence of rhupus is unknown. <h3>Objectives:</h3> To evaluate the prevalence of patients with rhupus syndrome in our tertiary care center. <h3>Methods:</h3> We chart-reviewed all patients with a diagnosis of SLE[1] or RA[2], based on the current ACR classification criteria, who presented to our outpatient clinic rheumatology unit. Clinical and laboratory data were retrospectively collected from patient notes. Diagnosis were systematically analyzed by two independent reviewers (SGF and ER). Disagreements were resolved by consensus; if consensus could not be achieved, a third party (SS) would provide an assessment of eligibility. <h3>Results:</h3> One-hundred eighty-two patients with a diagnosis of SLE and 253 patients of RA, were identified. Out of 182 SLE and 253 RA cases analysed, only 2 patients fulfilled rhupus criteria. The estimated prevalence in our cohort was 0.46% (2/437). In Figure 1 are illustrated the clinical manifestations of SLE (Panel A; Malar rash) and RA (radiograph-documented erosive polyarthritis) of the two patients. Additionally, we identified 7 patients (1.61% of the total cohort) that only partially fulfilled both criteria for SLE and RA. In detail, 1 patient (0.23%) manifested with an overlap of clinical manifestations of SLE and RA, while 1 patient had an overlap of both laboratory criteria. Two patients (0.46%) presented with clinical criteria of RA and laboratory criteria for SLE and RA and 3 patients (0.69%) with clinical criteria of SLE and laboratory criteria for SLE and RA. Patient's selection is resumed in Figure 2. <h3>Conclusion:</h3> The prevalence of rhupus observed in our study was relatively low (0.46%). However, we identified up to 1.6% of patients partially fulfilling a diagnosis of rhupus. Rhupus syndrome is a rare and aggressive clinical condition and further prospective studies and an harmonization of classification criteria are highly needed. <h3>References</h3> [1] Hochberg MC. Updating the ACR revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725. [2] Aletaha D, et al. 2010 rheumatoid arthritis classification criteria: an ACR/EULAR collaborative initiative. Ann Rheum Dis. 2010 Sep 1;69(9):1580–8. <h3>Disclosure of Interests:</h3> None declared
Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden
Authors: Yasmina Molero, Henrik Larsson, Brian M D’Onofrio, David J Sharp, Seena Fazel
Journal: BMJ (2019)

Abstract Objective To examine associations between gabapentinoids and adverse outcomes related to coordination disturbances (head or body injuries, or both and road traffic incidents or offences), mental health (suicidal behaviour, unintentional overdoses), and criminality. Design Population based cohort study. Setting High quality prescription, patient, death, and crime registers, Sweden. Participants 191 973 people from the Swedish Prescribed Drug Register who collected prescriptions for gabapentinoids (pregabalin or gabapentin) during 2006 to 2013. Main outcome measures Primary outcomes were suicidal behaviour, unintentional overdoses, head/body injuries, road traffic incidents and offences, and arrests for violent crime. Stratified Cox proportional hazards regression was conducted comparing treatment periods with non-treatment periods within an individual. Participants served as their own control, thus accounting for time invariant factors (eg, genetic and historical factors), and reducing confounding by indication. Additional adjustments were made by age, sex, comorbidities, substance use, and use of other antiepileptics. Results During the study period, 10 026 (5.2%) participants were treated for suicidal behaviour or died from suicide, 17 144 (8.9%) experienced an unintentional overdose, 12 070 (6.3%) had a road traffic incident or offence, 70 522 (36.7%) presented with head/body injuries, and 7984 (4.1%) were arrested for a violent crime. In within-individual analyses, gabapentinoid treatment was associated with increased hazards of suicidal behaviour and deaths from suicide (age adjusted hazard ratio 1.26, 95% confidence interval 1.20 to 1.32), unintentional overdoses (1.24, 1.19 to 1.28), head/body injuries (1.22, 1.19 to 1.25), and road traffic incidents and offences (1.13, 1.06 to 1.20). Associations with arrests for violent crime were less clear (1.04, 0.98 to 1.11). When the drugs were examined separately, pregabalin was associated with increased hazards of all outcomes, whereas gabapentin was associated with decreased or no statistically significant hazards. When stratifying on age, increased hazards of all outcomes were associated with participants aged 15 to 24 years. Conclusions This study suggests that gabapentinoids are associated with an increased risk of suicidal behaviour, unintentional overdoses, head/body injuries, and road traffic incidents and offences. Pregabalin was associated with higher hazards of these outcomes than gabapentin.
Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer
Authors: Young Kwang Chae, Pedro Viveiros, Gilberto Lopes, Bhoomika Sukhadia, Muhammad Mubbashir Sheikh, Diana Saravia, Vaia Florou, Ethan S. Sokol, Garrett M. Frampton, Zachary R. Chalmers, Siraj M. Ali, Jeffrey S. Ross, Sangmin Chang, Si Wang, Lauren Chiec, Ashkon Rahbari, Nisha Mohindra, Victoria Villaflor, Sang Ha Shin, Michael Oh, Jonathan Anker, Lee Chun Park, Victor Wang, Jeffrey Chuang, Wungki Park
Journal: Journal of Thoracic Oncology (2019)
Molecular and functional variation in iPSC-derived sensory neurons
Authors: Jeremy Schwartzentruber, Stefanie Foskolou, Helena Kilpinen, Julia Rodrigues, Kaur Alasoo, Andrew J. Knights, Minal Patel, Angela Goncalves, Rita Ferreira, Caroline Louise Benn, Anna Wilbrey, Magda Bictash, Emma Impey, Lishuang Cao, Sergio Lainez, Alexandre Julien Loucif, Paul John Whiting, Alex Gutteridge, Daniel J. Gaffney
Journal: Nature Genetics (2017)
Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases
Authors: Dipak Panigrahy, Allison Gartung, Jun Yang, Haixia Yang, Molly M. Gilligan, Megan L. Sulciner, Swati S. Bhasin, Diane R. Bielenberg, Jaimie Chang, Birgitta A. Schmidt, Julia Piwowarski, Anna Fishbein, Dulce Soler-Ferran, Matthew A. Sparks, Steven J. Staffa, Vidula Sukhatme, Bruce D. Hammock, Mark W. Kieran, Sui Huang, Manoj Bhasin, Charles N. Serhan, Vikas P. Sukhatme
Journal: Journal of Clinical Investigation (2019)

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.