tbuckley/cabot-search huggingface dataset:
Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming
Authors: Sylvain Carras, Dimitri Chartoire, Sylvain Mareschal, Maël Heiblig, Antoine Marçais, Rémy Robinot, Mirjam Urb, Roxane M. Pommier, Edith Julia, Amel Chebel, Aurélie Verney, Charlotte Bertheau, Emilie Bardel, Caroline Fezelot, Lucien Courtois, Camille Lours, Alyssa Bouska, Sunandini Sharma, Christine Lefebvre, Jean-Pierre Rouault, David Sibon, Anthony Ferrari, Javeed Iqbal, Laurence de Leval, Philippe Gaulard, Alexandra Traverse-Glehen, Pierre Sujobert, Mathieu Blery, Gilles Salles, Thierry Walzer, Emmanuel Bachy, Laurent Genestier
Journal: Journal of Clinical Investigation (2021)

Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell–like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.
AB0051 SEMAPHORIN 3A: A POSSIBLE MARKER FOR DISEASE ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: Ahmed Abdelaziz, Shereen Kaddafy, Salwa Fayez, Enas Gomaa, Fadwa Abdelreheem
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Sema 3A is concerned in the pathogenesis of many autoimmune diseases because it is involved in regulation of immune responses and maintenance of self-tolerance. Regulatory T cells play an important role in maintaining immunological self-tolerance by suppressing autoreactive T cells. Sema3A promotes regulatory T cells by enhancing IL-10 production <h3>Objectives:</h3> The current study aimed at testing the possible role of Semaphorin 3A (Sema 3A) in activity and in remission in rheumatoid arthritis patients and to assess whether this level correlates with interleukin 10 (IL-10) level. <h3>Methods:</h3> Sixty Egyptian patients with rheumatoid arthritis (RA) were divided into three groups according to modified Disease Activity Score (DAS28), RA in high activity (group II, n=20), RA in moderate activity (group III, n=20) and RA in remission (group IV, n=20) and compared with 20 normal individuals (group I). Serum levels of Sema 3A and IL-10 were measured and correlated with ESR, CRP, Rheumatoid factor, DAS28 and Health Assessment Questionnaire (HAQ). <h3>Results:</h3> Serum Sema 3A levels were significantly lower in high activity (55.7 ± 15.5 pg/ml) than in moderate activity groups (72.9 ± 14.6 pg/ml, p = 0.002) and both levels are lower than those in remission group (77.2 ± 13.1pg/ml, p &lt; 0.001 compared to high activity one) and the control groups (76.5 ± 23.6pg/ml, p &lt; 0.001 compared to high activity one also), A significant negative correlation was detected between Sema 3A and each of ESR, CRP, DAS28 and HAQ. Serum IL-10 was higher in patient groups, with highest mean among group IV. Conclusion: reduced serum level of Sema 3A was found to be correlated with disease activity and indicating its usefulness marker for RA disease activity. <h3>Disclosure of Interests:</h3> None declared
Characterization of structural variation in Tibetans reveals new evidence of high-altitude adaptation and introgression
Authors: Cheng Quan, Yuanfeng Li, Xinyi Liu, Yahui Wang, Jie Ping, Yiming Lu, Gangqiao Zhou
Journal: Genome biology (2021)

Structural variation (SV) acts as an essential mutational force shaping the evolution and function of the human genome. However, few studies have examined the role of SVs in high-altitude adaptation and little is known of adaptive introgressed SVs in Tibetans so far.Here, we generate a comprehensive catalog of SVs in a Chinese Tibetan (n = 15) and Han (n = 10) population using nanopore sequencing technology. Among a total of 38,216 unique SVs in the catalog, 27% are sequence-resolved for the first time. We systematically assess the distribution of these SVs across repeat sequences and functional genomic regions. Through genotyping in additional 276 genomes, we identify 69 Tibetan-Han stratified SVs and 80 candidate adaptive genes. We also discover a few adaptive introgressed SV candidates and provide evidence for a deletion of 335 base pairs at 1p36.32.Overall, our results highlight the important role of SVs in the evolutionary processes of Tibetans' adaptation to the Qinghai-Tibet Plateau and provide a valuable resource for future high-altitude adaptation studies.
Robustness of Phylogenetic Inference to Model Misspecification Caused by Pairwise Epistasis
Authors: Andrew F Magee, Sarah K Hilton, William S DeWitt
Journal: Molecular Biology and Evolution (2021)

Likelihood-based phylogenetic inference posits a probabilistic model of character state change along branches of a phylogenetic tree. These models typically assume statistical independence of sites in the sequence alignment. This is a restrictive assumption that facilitates computational tractability, but ignores how epistasis, the effect of genetic background on mutational effects, influences the evolution of functional sequences. We consider the effect of using a misspecified site-independent model on the accuracy of Bayesian phylogenetic inference in the setting of pairwise-site epistasis. Previous work has shown that as alignment length increases, tree reconstruction accuracy also increases. Here, we present a simulation study demonstrating that accuracy increases with alignment size even if the additional sites are epistatically coupled. We introduce an alignment-based test statistic that is a diagnostic for pairwise epistasis and can be used in posterior predictive checks.
POS1275 PERITENON THICKENING IS ASSOCIATED WITH THE INTENSITY OF MANUAL SPORTS ACTIVITY
Authors: C. Guillén-Astete, P. Zurita-Prada, C. Urrego-Laurín, N. García-Montes, H. García-López
Journal: Annals of the Rheumatic Diseases (2021)

Background: Peritenon enlargement has been considered as a specific ultrasound finding associated with psoriatic arthritis based on studies in patients. Recent observations in athletes have demonstrated the existence of this finding although its relationship with the type of physical activity performed has not been determined. Objectives: To determine to what extent manual physical activity is associated with the prevalence of peritenon thickening in the fingers of healthy athletic subjects. Methods: Thirty-five healthy young male volunteers were recruited from a local sports centre in the community of Madrid. All of them performed sports activities with their hands for more than 12 hours a week.A digital dynamometer was used to determine the flexion strength of the fingers of the dominant hand. A single observer performed an ultrasound scan of this hand to determine the presence or absence of a hypoechoic image surrounding the extensor digitorum tendon of the 2nd, 3rd, 4th and 5th fingers, according to previous definitions. Mean flexion strengths were compared with the number of positive ultrasound findings. Results: Fifteen volunteers (mean age 24.3 years, BMI 24.4) did not present peritenon enlargement (42.8%). The mean ± standard deviation of the fingers flexor strength according to the number of peritenon enlargement detected were 43.5 ± 6.2, 49.2 ± 3.8, 53.2 ± 1.64 and 63.0 ± 4.83 Kg for volunteers with none, 1, 2, 3 and 4 peritenon enlargements, respectively. (ANOVA P&lt;0.001; Pearson’s coefficient 0.827, P&lt;0.001). Correlation between BMI, body fat percentage or training hours per week and the number of peritenon enlargement detected was not demonstrated. Conclusion: Peritenon enlargement, also knew as peritenon tendon inflammation, is detectable by ultrasound scan in healthy subjects and it seems to be associated to the physical activity intensity, indirectly measured by the flexor strength of the fingers. References: [1]Gutierrez et al. Ann Rheum Dis. 2011;70:1111-4 [2]Zabotti et al. Clin Exp Rheumatol. 2016;34:459-65 [3]Husic et al. Ann Rheum Dis. 2014;73:1529-36 Disclosure of Interests: None declared
Single dose of BNT162b2 mRNA vaccine against SARS-CoV-2 induces high frequency of neutralising antibody and polyfunctional T-cell responses in patients with myeloproliferative neoplasms
Authors: Patrick Harrington, Hugues de Lavallade, Katie J. Doores, Amy O’Reilly, Jeffrey Seow, Carl Graham, Thomas Lechmere, Deepti Radia, Richard Dillon, Yogita Shanmugharaj, Andreas Espehana, Claire Woodley, Jamie Saunders, Natalia Curto-Garcia, Jennifer O’Sullivan, Kavita Raj, Shahram Kordasti, Michael H. Malim, Claire N. Harrison, Donal P. McLornan
Journal: Leukemia (2021)
AB0696 ANTI-PHOSPHOLIPID AUTOANTIBODIES IN COVID-19 PATIENTS
Authors: M. Jordhani, D. Ruci, V. Ruci
Journal: Annals of the Rheumatic Diseases (2021)

Background: Because of the inflammation boosting cytokines, Coronavirus disease 2019 (COVID-19) has demonstrated thrombotic consequences that have increased its morbidity and mortality. There is evidence that mechanisms that contribute in thrombosis in COVID-19 patients are similar to those in anti-phospholipid syndrome (aPS). In fact, there is a possibility that anti-phospholipid autoantibodies (aPLs) might impulse thrombosis in patients with COVID-19, as literature suggests 2 . Objectives: The aim of our study was to evaluate the anti-phospholipid autoantibody titre in patients with COVID-19 during and after the infection. Methods: This is an observational study which included 71 patients with a recent COVID-19 up to 4 weeks after. Every patient was completed with aPL titre about IgG and IgM anti-cardiolipine (ACA) and lupus anticoagulant (LAC) autoantibodies. According to titre results, the patients were divided into groups in order to better show the immunologic results. Results: After gathering and analysing the data, it was estimated that 21 patients (29.6%) were positive for at least one type of aPL antibody: 12 patients were found positive for lupus anticoagulant autoantibodies (57.1%), 6 patients were double positive for LAC and ACA (28.6%), and 3 patients were positive for anti-cardiolipin antibodies (14.3%). Seven patients were IgM positive for any aPL (33.3%), 6 patients were found to have positive IgM and IgG (28.6%) and 8 patients had only IgG antibodies (38.1%). Conclusion: From this study it was observed that a significant proportion of patients with recent COVID-19 infection had positive anti-phospholipid antibodies, compared to the general population prevalence. This suggests that the impact of aPLs in COVID-19 might be of great importance. It should be carefully evaluated in order to better understand the mechanisms of thrombotic complications. References: [1]Wise Jacqui. Covid-19 and thrombosis: what do we know about the risks and treatment? BMJ 2020; 369:m2058 [2]Zuo, Yu, et al. “Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.” Science translational medicine 12.570 (2020). Disclosure of Interests: None declared
AB0659 THE LOCKDOWN REPERCUSSION ON THE RHEUMATOLOGIST’S LIFE
Authors: P. Lemesle, L. Poulain, X. Grapton, N. Bouhedja
Journal: Annals of the Rheumatic Diseases (2021)

Background: We have just experienced an exceptional period of time and it seemed interesting to know what this particular time of isolation in a population of rheumatologists has brought about Objectives: To analyze what the doctor felt in his personal and professional life as a result of the crisis. To determine the reactions, feelings and attitudes that may have emerged during these weeks of confinement. Methods: 38 private practice rheumatologists from the Ile-de-France region, average age 63 yo, 58% male (M). 13 questions, 9 appendices, ranking of the most frequently cited reactions Results: 3 feelings stand out: anger 71-84%, fear of being contaminated and of transmitting M 91/F 69%, concern about an unknown pandemic M 86/F69%. Anger at the indifference to the exposure of doctors in the city 84%, the unpreparedness of the authorities M 95/F 62%, the mortality in EHPAD (Nursing homes) 81%, the media cacophony 79%, the hidden reality 71%. On a personal level, according to 61%, the Rh is not anxious about the world after, has no psychological repercussions (sleep, melancholy, etc.) 58% and his degree of commitment was guilt-free 55%. Professionally: perplexity in the face of the contradictions of experts and scientific journals 79%, wide acceptance of constraints in the practice (10h/d mask wearing, 92%, spaced reception of patients 95%, education of barrier gestures 97%), adaptation of the exercise (teleconsultation, telephone consultation) 78%, fear of abandoning treatment or diagnostic delay M82/F62%, financial arrangements necessary M86/F53%. For M: worries about the pandemic, anger and uncertainty about what will happen next predominate in this order. For F, anger (untruths and lack of means) is the main feeling. Anger, fear and uncertainty are the most frequently cited feelings Conclusion: The Rh at the end of this period of confinement is worried M&gt;F and anger especially in front of the sanitary unpreparedness M&gt;F. On a personal level the private life has been little affected F&gt;M and he has been able to adapt professionally. Nevertheless, the de-confinement has not been a banal return to normal 63% M= F. Disclosure of Interests: None declared.
Dermatology Advances Into an Era of Precision Medicine
Authors: Jennifer Y. Wang, Kavita Y. Sarin
Journal: JAMA Dermatology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Anti-Inflammatory Drugs Remodel the Tumor Immune Environment to Enhance Immune Checkpoint Blockade Efficacy
Authors: Victoria S. Pelly, Agrin Moeini, Lisanne M. Roelofsen, Eduardo Bonavita, Charlotte R. Bell, Colin Hutton, Adrian Blanco-Gomez, Antonia Banyard, Christian P. Bromley, Eimear Flanagan, Shih-Chieh Chiang, Claus Jørgensen, Ton N. Schumacher, Daniela S. Thommen, Santiago Zelenay
Journal: Cancer Discovery (2021)

Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX2/PGE2/EP2-4 pathway with widely used nonsteroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from nonresponders shortly after treatment and identified acute IFNγ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T-cell activation. Our findings establish the COX2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot. SIGNIFICANCE: Through performing in-depth profiling of mice and human tumors, this study identifies mechanisms by which anti-inflammatory drugs rapidly alter the tumor immune landscape to enhance tumor immunogenicity and responses to immune checkpoint inhibitors.See related commentary by Melero et al., p. 2372.This article is highlighted in the In This Issue feature, p. 2355.
Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo
Authors: Souvarish Sarkar, Farah Bardai, Abby L. Olsen, Kelly M. Lohr, Ying-Yi Zhang, Mel B. Feany
Journal: Molecular Neurodegeneration (2021)

Abstract Background Mutations in LRRK2 are the most common cause of familial Parkinson’s disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue. Methods We combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human α-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models. Results We demonstrate that Lrrk and α-synuclein interact to promote neuronal degeneration through convergent effects on the actin cytoskeleton and downstream dysregulation of mitochondrial dynamics and function. We find specifically that monomers and dimers of Lrrk efficiently sever actin and promote normal actin dynamics in vivo. Oligomerization of Lrrk, which is promoted by dominant Parkinson’s disease-causing mutations, reduces actin severing activity in vitro and promotes excess stabilization of F-actin in vivo. Importantly, a clinically protective Lrrk mutant reduces oligomerization and α-synuclein neurotoxicity. Conclusions Our findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson’s disease, α-synuclein and LRRK2, and suggest potential new approaches for therapy development.
The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma
Authors: Mukesh Verma, Lidia Michalec, Anand Sripada, Jerome McKay, Kapil Sirohi, Divya Verma, Dipa Sheth, Richard Martin, Nathan Dyjack, Max A. Seibold, Jennifer R. Knapp, Ting-Hui Tu, Brian P. O’Connor, Magdalena M. Gorska, Rafeul Alam
Journal: The Journal of Experimental Medicine (2021)

Repetitive exposure of Rag1−/− mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3–15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma. ATAC-seq demonstrated a distinct epigenetic landscape of memory ILC2s and identified Bach2 and AP1 (JunD and Fosl2) motifs as major drivers of altered gene accessibility. scRNA-seq, gene knockout, and signaling studies suggest that repetitive allergenic stress induces a gene repression program involving Nr4a2, Zeb1, Bach2, and JunD and a preparedness program involving Fhl2, FosB, Stat6, Srebf2, and MPP7 in memory ILC2s. A mutually regulated balance between these two programs establishes and maintains memory. The preparedness program (e.g., Fhl2) can be activated with a subthreshold cognate stimulation, which down-regulates repressors and activates effector pathways to elicit the memory-driven phenotype.
Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a<i>Post Hoc</i>Analysis of the PRODIGE-GERCOR IDEA-France Trial
Authors: Julien Taieb, Valérie Taly, Julie Henriques, Camille Bourreau, Laurent Mineur, Jaafar Bennouna, Jérôme Desrame, Christophe Louvet, Céline Lepere, May Mabro, Joëlle Egreteau, Olivier Bouche, Claire Mulot, Katia Hormigos, Kariman Chaba, Thibault Mazard, Aimery de Gramont, Dewi Vernerey, Thierry André, Pierre Laurent-Puig
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial. Experimental Design: ctDNA was tested for WIF1 and NPY by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III). Results: Of 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (n = 1017) versus not analyzed (n = 993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (P = 0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR = 1.55, 95% CI 1.13–2.12, P = 0.006) and OS (HR = 1.65, 95% CI 1.12–2.43, P = 0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1–3/N1 tumors. Conclusions: In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker. See related commentary by Bent and Kopetz, p. 5449
Optimal cervical screening COVID-19 recovery strategies in high-income countries depend on context of current programme organisation
Authors: Alejandra Castanon, Matejka Rebolj, Emily Burger, Inge M.C.M de Kok, Megan Smith, Sharon J.B. Hanley, Francesca Maria Carozzi, Stuart Peacock, James F O'Mahony
Journal: The Lancet Public Health (2021)