tbuckley/cabot-search huggingface dataset:
Coronavirus-specific antibody production in middle-aged mice requires phospholipase A2G2D
Authors: Jian Zheng, David Meyerholz, Lok-Yin Roy Wong, Michael Gelb, Makoto Murakami, Stanley Perlman
Journal: Journal of Clinical Investigation (2021)

Worse outcomes occur in aged compared with young populations after infections with respiratory viruses, including pathogenic coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), and are associated with a suboptimal lung milieu ("inflammaging"). We previously showed that a single inducible phospholipase, PLA2G2D, is associated with a proresolving/antiinflammatory response in the lungs, and increases with age. Survival was increased in naive Pla2g2d–/– mice infected with SARS-CoV resulting from augmented respiratory dendritic cell (rDC) activation and enhanced priming of virus-specific T cells. Here, in contrast, we show that intranasal immunization provided no additional protection in middle-aged Pla2g2d–/– mice infected with any of the 3 pathogenic human coronaviruses because virtually no virus-specific antibodies or follicular helper CD4+ T (Tfh) cells were produced. Using MERS-CoV–infected mice, we found that these effects did not result from T or B cell intrinsic factors. Rather, they resulted from enhanced, and ultimately, pathogenic rDC activation, as manifested most prominently by enhanced IL-1β expression. Wild-type rDC transfer to Pla2g2d–/– mice in conjunction with partial IL-1β blockade reversed this defect and resulted in increased virus-specific antibody and Tfh responses. Together, these results indicate that PLA2G2D has an unexpected role in the lungs, serving as an important modulator of rDC activation, with protective and pathogenic effects in respiratory coronavirus infections and immunization, respectively.
<i>CDKN2A</i> Alterations and Response to Immunotherapy in Solid Tumors
Authors: Elio Adib, Amin H. Nassar, Elie W. Akl, Sarah Abou Alaiwi, Pier Vitale Nuzzo, Tarek H. Mouhieddine, Guru Sonpavde, Robert I. Haddad, Kent W. Mouw, Marios Giannakis, F. Stephen Hodi, Sachet A. Shukla, Alexander Gusev, David A. Braun, Toni K. Choueiri, David J. Kwiatkowski
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Immune checkpoint inhibitors (ICI) have shown clinical benefit in many types of metastatic cancers with only a few predictive biomarkers identified so far. CDKN2A is commonly altered in human cancers, but prior studies have provided conflicting evidence regarding the association between CDKN2A genomic alterations (GA) and response to ICIs. Herein, we examined the impact of loss-of-function CDKN2A alterations on response and survival in patients treated with ICIs. Experimental Design: We studied the association between loss-of-function CDKN2A alterations and the response to ICIs in two independent cohorts of six different cancer types. Seven hundred and eighty-nine patients treated at Dana-Farber Cancer Institute (DFCI; Boston, MA) and 1,250 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY) were included in the final analysis. Patients' tumors were sequenced using Oncopanel or MSK-IMPACT. RNA sequencing data from The Cancer Genome Atlas and IMvigor210 were used to investigate differences in the tumor microenvironment. Results: In the DFCI cohort, CDKN2A GAs were associated with poor response and survival in patients with urothelial carcinoma treated with ICIs, but not those treated with platinum-based therapy. Similarly, CDKN2A GAs were associated with worse outcomes in the MSKCC urothelial carcinoma cohort treated with ICIs. There was no association of CDKN2A status with ICI treatment outcome in five other cancers: esophagogastric, head and neck, non–small cell lung, renal cell carcinoma, and melanoma. Immuno-inflammatory pathways were significantly reduced in expression in CDKN2A-altered tumors. Conclusions: Our data show that CDKN2A GAs were associated with reduced benefit from ICI therapy in urothelial carcinoma as well as changes in the tumor–immune microenvironment.
Time to Reconsider the Importance of Autonomic Function in Paralympic Athletes With Spinal Cord Injury
Authors: Abdullah A. Alrashidi, Tom E. Nightingale, Andrei V. Krassioukov
Journal: JAMA Cardiology (2021)

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POS1346 CLINICAL ASSOCIATIONS OF ANTI-RO52 ANTIBODIES IN PATIENTS WITH SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES
Authors: D. Prieto-Peña, B. Atienza-Mateo, M. A. González-Gay, R. Blanco, M. Lopez-Hoyos
Journal: Annals of the Rheumatic Diseases (2021)

Background: Anti-SSA/Ro antibodies (Abs) can target Ro60 and Ro52 antigens. The presence of anti-Ro60 Abs has been widely described in patients with systemic autoimmune rheumatic diseases (SARDs). However, the clinical implication of anti-Ro52 Abs for the diagnosis and management of SARDs remains unclear. Objectives: To assess the clinical associations of anti-Ro52 antibodies in patients with high clinical suspicion of SARDs. Methods: We retrieved the clinical records of all patients with positive anti-Ro52 Abs tested in our hospital between November 2017 and September 2020. Patients were divided into 3 groups: 1) anti-Ro52+Ro60 + 2) antiRo52+Ro60- 3) antiRo52+Ro60+ with other Abs. A comparative study between groups was performed. Results: 57 patients (43 women/14 men; mean age 62.1±13.6 years) with antiRo52+ Abs were identified. Final diagnosis were: undifferentiated connective tissue disease (UCTD) (n=13), anti-synthetase/overlap myositis (n=12), Sjögren’s syndrome (n=7), interstitial pneumonia with autoimmune features (IPAF) (n=6), scleroderma (n=4), systemic lupus erythematosus (n=2), dermatomyositis (n=2), other systemic inflammatory diseases (n=3). In 8 (14%) patients the diagnosis of inflammatory diseases was finally ruled out. 27 patients were classified in the Ro52+Ro60+ group, 11 in the Ro52+Ro60- group and 19 Ro52+ with other Abs. Patients with Ro52+Ro60- were younger and more often women than patients with Ro52+Ro60+.Interstitial lung disease (ILD) was less frequent in patients with Ro52+Ro60-(Table 1 ). Isolated Ro52 Abs were more frequently associated with UCTD, while IPAF was more commonly found in patients with anti-Ro52+Ro60+ Abs (Table 1 and Figure 1). Figure 1. Conclusion: Anti Ro52 Abs determination has clinical implications in the diagnosis of SARDs. Table 1. Anti-Ro52+Ro60+ (n=27) Anti-Ro52+Ro60 - (n=11) Anti-Ro52+Ro60+ with other Abs (n=19) Age (years), mean ± SD 65.7 ± 10.0 53.8 ± 18.0 * 61.7 ± 13.6 Sex (females), n (% ) 19 (70.4) 10 (90.9) * 14 (73.7) Clinical manifestations at anti-Ro52 determination , n (%) Arthralgias/arthritis 18 (66.7) 7 (63.6) 14 (73.7) Raynaud’s phenomenon 9 (33.3) 4 (36.4) 9 (47.4) Myopathy 4 (14.8) 1 (9.1) 2 (10.5) Final diagnosis , n (%) Systemic lupus erythematosus 0 (0) 0 (0) 2 (10.5) Sjögren’s syndrome 3 (11.1) 1 (9.1) 4 (21.1) Scleroderma 1 (3.7) 0 3 (15.8) Undifferentiated connective tissue disease 3 (11.1) 7 (63.6) ** 3 (15.8) Overlap myositis 7 (25.9) 1 (9.1) 4 (21.1) Dermatomyositis 1 (3.7) 0 1 (5.3) IPAF 5 (18.5) ** 0 0 Other systemic inflammatory diseases 3 (11.1) 0 0 Non inflammatory disease 4 (14.8) 2 (18.2) 2 (10.5) Comorbidities, n (%) ILD 11 (40.7) 1 (9.1) ** 7 (36.8) Malignancy 5 (18.5) 1 (9.1) 0 (0.0) * p&lt; 0.05 (Ro52+Ro60+ vs Ro52+Ro60-) ** p&lt; 0.05 (Ro52+Ro60+ vs Ro52+ Ro60 - vs Ro52+Ro60+ with other Abs) Disclosure of Interests: None declared
AB0614 DENSITOMETRIC VERTEBRAL FRACTURE ASSESSMENT: FACTORS LIMITING GOOD VISIBILITY OF THE VERTEBRA
Authors: S. Mariem, M. Yasmine, S. Miladi, A. Fazaa, E. Frigui, L. Souebni, K. Ouenniche, S. Kassab, S. Chekili, K. Ben Abdelghani, A. Laatar
Journal: Annals of the Rheumatic Diseases (2021)

Background: The radiograph of the spine is the gold standard for identifying vertebral fractures (VF). Vertebral Fracture Assessment (VFA) is a new feature available on modern densitometers that could assess VF. This technique offers the advantage of low irradiation over standard radiography but at the cost of lower image quality. Objectives: The aim of this study was to assess factors associated with good vertebra visibility when using VFA. Methods: This is a cross-sectional study including patients referred by their physicians for bone mineral density (BMD) measurement. Anthropometric data were recorded. BMD was measured using standard methods over the lumbar spine L1-L4, the total proximal femur. Results were expressed as T-scores using Dual-energy X-ray absorptiometry (DEXA). The screening for VF was performed by VFA. A professional operator analyses VFA scans and assessed the good visibility of the vertebra. Results: The study included 100 patients. The mean age was 61.7 ±12.6 years [18-83].The average body mass index (BMI) was 28.9 ± 24.2 kg/m2 [14.2-45.3]. The mean T-score at the vertebral site was -1.5 DS [-4.9-1.5] with a mean mass of 0.95g/cm 2 [0.58-1.371]. Osteoporosis was found in 27.7 % of patients. A vertebral fracture was diagnosed in 25% of cases. The visualization of the vertebra was impaired in the upper thoracic region in 60% of cases. Poor visibility was observed in 19% of cases in the mid-thoracic spine and only in 2% of cases in the lumbar spine. No statistically significant correlation was found between good vertebral visibility and age (p=0.2), weight (p=0.5), or BMI (p=0.7). However, good visibility of the vertebra was associated with a lower height (1.7 m vs 1.5 m, p=0.03). A better vertebrae visualization was correlated neither to the BMD of the right hip (0.84 vs 0.87, p=0.4) nor to the left hip (0.85 vs 0.89, p= 0.3). Similarly, the absence of vertebral osteoporosis was not correlated with a better vertebral visualization (p=0.6). Conclusion: Visibility of the vertebra on VFA does not appear to be altered by the BMD and vertebral osteoporosis, suggesting safe use in the elderly. However, precautions may be taken when interpreting VFA in patients with high heights. Disclosure of Interests: None declared.
Identifying patients in outpatient clinics must be improved, says safety watchdog
Authors: Clare Dyer
Journal: BMJ (2021)

England’s healthcare safety watchdog has called for action to tighten up systems in outpatient settings after the wrong patient underwent an invasive procedure.1

The Healthcare Safety Investigation Branch launched a national investigation after a 39 year old woman who attended a gynaecology clinic at a large district general hospital to discuss fertility treatment was given a colposcopy meant for another patient.

Investigators found that although national guidance was in place to ensure proper identification of hospital patients, there was little research or writing on patient safety in outpatient settings. Yet visits to outpatient clinics had nearly …
Residual SARS-CoV-2 viral antigens detected in GI and hepatic tissues from five recovered patients with COVID-19
Authors: Chun Chau Lawrence Cheung, Denise Goh, Xinru Lim, Tracy Zhijun Tien, Jeffrey Chun Tatt Lim, Justina Nadia Lee, Benedict Tan, Zhi En Amos Tay, Wei Yee Wan, Eileen Xueqin Chen, Sanjna Nilesh Nerurkar, Shihleone Loong, Peng Chung Cheow, Chung Yip Chan, Ye Xin Koh, Thuan Tong Tan, Shirin Kalimuddin, Wai Meng David Tai, Jia Lin Ng, Jenny Guek-Hong Low, Joe Yeong, Kiat Hon Lim
Journal: Gut (2021)

<b>When a patient is diagnosed with IPF, the net health costs increase from €2753 to €21 184 per year even without the cost of antifibrotic treatment. Inpatient treatment accounts for the main part of the expenses</b>http://ow.ly/dSsn30jEx0p
Step-by-step Development of a Cold Ischemia Device for Open and Robotic-assisted Renal Transplantation
Authors: Angelo Territo, Alberto Piana, Matteo Fontana, Pietro Diana, Andrea Gallioli, Josep Maria Gaya, Jordi Huguet, Pavel Gavrilov, Óscar Rodríguez-Faba, Carmen Facundo, Lluis Guirado, Joan Palou, Alex Mottrie, Alberto Breda
Journal: European Urology (2021)
Sex-Dependent Effects of Nephron Ift88 Disruption on BP, Renal Function, and Cystogenesis
Authors: Chunyan Hu, Jayalakshmi Lakshmipathi, Elizabeth Binning, Kelly A. Hyndman, Deborah Stuart, Donald E. Kohan
Journal: Journal of the American Society of Nephrology (2021)

Primary cilia regulation of renal function and BP in health and disease is incompletely understood. This study investigated the effect of nephron ciliary loss on renal physiology, BP, and ensuing cystogenesis.Mice underwent doxycycline (DOX)-inducible nephron-specific knockout (KO) of the Ift88 gene at 2 months of age using a Cre-LoxP strategy. BP, kidney function, and renal pathology were studied 2 and 9 months after DOX (Ift88 KO) or vehicle (control).At 2 months post-DOX, male, but not female, Ift88 KO, compared with sex-matched control, mice had reduced BP, enhanced salt-induced natriuresis, increased urinary nitrite and nitrate (NOx) excretion, and increased kidney NOS3 levels, which localized to the outer medulla; the reductions in BP in male mice were prevented by L-NAME. At 9 months post-DOX, male, but not female, Ift88 KO mice had polycystic kidneys, elevated BP, and reduced urinary NOx excretion. No differences were observed in plasma renin concentration, plasma aldosterone, urine vasopressin, or urine PGE2 between Ift88 KO and control mice at 2 or 9 months post-DOX.Nephron cilia disruption in male, but not female, mice (1) reduces BP prior to cyst formation, (2) increases NOx production that may account for the lower BP prior to cyst formation, and (3) induces polycystic kidneys that are associated with hypertension and reduced renal NO production.
AB0540 COMPARISON OF EQ-5D HEALTH STATUS IN PSORIATIC ARTHRITIS PATIENTS WITH OR WITHOUT AXIAL DISEASE: RESULTS OF SUBANALYSIS OF THE PATERA STUDY
Authors: I. Gaydukova, T. Korotaeva, V. Mazurov, A. Samtsov, V. Khayrutdinov, A. Bakulev, A. Kundzer, N. Soroka, A. Eremeeva
Journal: Annals of the Rheumatic Diseases (2021)

Background: Netakimab (NTK) is an anti-interleukin-17A monoclonal antibody approved for psoriasis, ankylosing spondylitis, psoriatic arthritis (PsA) in Russia and Belarus. PATERA is an ongoing phase 3 international double-blind, placebo-controlled clinical study of NTK in PsA ( NCT03598751 ). Objectives: A subanalysis was performed to assess the effect of NTK on domains of the 5-level EuroQol 5 Dimensions questionnaire (EQ-5D-5L) in patients with inflammatory back pain (IBP) (IBP(+)) and without (IBP(-)) at baseline according to self-reported ASAS IBP criteria, 2009. Methods: 194 adult patients with PsA (CASPAR criteria, 2006) with inadequate response to csDMARD or one TNFi, were randomly assigned to receive NTK 120mg or placebo at weeks 0,1,2,4,6,8,10,14,18,22. The proportion of patients reported &gt;1 problem in each domain was evaluated. Patients with missing values were considered as non-responders in the analysis. Results: 97 PsA patients (N=54 IBP(+), N=43 IBP(-)) received NTK. The subpopulations didn’t differ significantly in gender, age, and PsA activity at baseline. Comparable percentage of patients reported any problems for each domain at baseline (p≥0.05) (data not shown). IBP(-) subpopulation had a greater improvement for all domains except of anxiety/depression. The absolute declines for IBP(+) vs IBP(-) patients were as followed: 24.1% vs 41.9% (mobility), 18.5 vs 41.9% (self-care), 24.0% vs 51.1% (usual activities), 24.1% vs 37.2% (pain/discomfort), 33.3% vs 9.3% (anxiety/depression). However, the only significant difference between IBP(+) and IBP(-) was observed in usual activity (Figure 1). Conclusion: NTK resulted in the growing improvement of each EQ-5D-5L domain through 24 weeks irrespectively of the presence of IBP. IBP(-) subjects showed trend to greater benefit compared to IBP(+). Figure 1 Percentage of patients reported any problems in (A) pain/discomfort, (B) in usual activity at each visit Acknowledgements: This study was sponsored by JSC BIOCAD. Disclosure of Interests: Inna Gaydukova Speakers bureau: Abbvie, Biocad, Eli Lilly, MSD, Novartis, Pfizer, Sandoz, Tatiana Korotaeva Speakers bureau: Abbvie, Biocad, Eli Lilly, Johnson &amp; Johnson, Janssen, Novartis, Pfizer, UCB, V Mazurov: None declared., Aleksey Samtsov: None declared., Vladislav Khayrutdinov: None declared., Andrey Bakulev: None declared., Alena Kundzer: None declared., Nikolaj Soroka: None declared., Anna Eremeeva Employee of: Biocad.
Abstract 15909: Impaired Peripheral Microvascular Function and Risk of Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease
Authors: An Young, Samaah Sullivan, Bruno B Lima, Chang Liu, Muhammad Hammadah, Yi-An Ko, Amit J Shah, Jeong Hwan Kim, Kasra Moazzami, Mhmtjamil Alkhalaf, J Douglas Bremner, Paolo Raggi, Arshed A Quyyumi, Viola Vaccarino
Journal: Circulation (2019)

Introduction: In patients with coronary artery disease (CAD), the risk of recurrent adverse cardiovascular (CV) events remains elevated despite treatment. The role played by impaired microvascular ...
Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity
Authors: Yugang Guo, Yu-Qing Xie, Min Gao, Yang Zhao, Fabien Franco, Mathias Wenes, Imran Siddiqui, Alessio Bevilacqua, Haiping Wang, Hanshuo Yang, Bing Feng, Xin Xie, Catherine M. Sabatel, Benjamin Tschumi, Amphun Chaiboonchoe, Yuxi Wang, Weimin Li, Weihua Xiao, Werner Held, Pedro Romero, Ping-Chih Ho, Li Tang
Journal: Nature Immunology (2021)
POS1274 THERAPEUTIC MANAGEMENT OF RHEUMATOLOGISTS VERSUS OTORHINOLARYNGOLOGISTS OF CERVICOGENIC DIZZINESS
Authors: M. Yasmine, K. Maatallah, H. Ferjani, W. Triki, D. Ben Nsib, D. Kaffel, W. Hamdi
Journal: Annals of the Rheumatic Diseases (2021)

Background: The treatment of patients presenting with cervicogenic dizziness (CGD) may be challenging. Indeed, there is no consensual treatment approach for CGD, nor is there no gold-standard assessment for diagnosis. Objectives: Our study aimed to assess the management of CGD by rheumatologists versus otorhinolaryngologists. Methods: We conducted a cross-sectional study including Tunisian doctors dealing with CGD. Rheumatologists (RTO) and otorhinolaryngologists (ORL) were invited to answer a questionnaire via google form about CGD daily management. Outcomes of interest were treatment modalities. Results: The study included 30 RTO and 32 ORL. Most of the doctors (RTO, vs ORL) were females (88.3%, vs 56.3%), aged between 35 and 45 (43.3%, vs 62.5%), and worked at a private practice (33.3%, vs 59.4%). The number of patients diagnosed with CGD by RTO was as follows: 1-2 per year (33.3%), 1-2 per month (18.8%), 1-2 per week (20%), less than one patient a year (10%) and none in 3.3% of cases. The number of patients diagnosed with CGD by ORL was as follows: 1-2 per year (50%), 1-2 per month (33.3%), 1-2 per week (6.2%), less than one patient a year (15.7%) and none (9.4%). Most patients presenting with CGD were females in both groups (93.1%, vs 82.8% respectively) with a mean age between 36 and 65 (79.3%, vs 82.1%). Most of the respondents declared treating patients with CGD (93.1%, vs 79.1%). Regarding treatment modalities, physical therapy was the most prescribed in both specialties (81.5% and 48.3%, respectively). Only RTO (18.5%) prescribed manual therapy. Concerning medical treatment, anti-inflammatory were the most prescribed drugs in both groups (92.6, and 34.5%, respectively). Sixty-seven percent of RTO prescribed anti-vertigo medication. Interestingly, it was the least prescribed drug by ORL (6.9%). Only RTO (59.3%) prescribed Muscle relaxants. Conclusion: Despite the disparities in the management of CGD, physical therapy remains the first prescribed treatment by Tunisian doctors. Further studies are needed to establish a consensus to treat CGD. Disclosure of Interests: None declared
Hard wiring of normal tissue-specific chromosome-wide gene expression levels is an additional factor driving cancer type-specific aneuploidies
Authors: Sushant Patkar, Kerstin Heselmeyer-Haddad, Noam Auslander, Daniela Hirsch, Jordi Camps, Daniel Bronder, Markus Brown, Wei-Dong Chen, Rachel Lokanga, Darawalee Wangsa, Danny Wangsa, Yue Hu, Annette Lischka, Rüdiger Braun, Georg Emons, B. Michael Ghadimi, Jochen Gaedcke, Marian Grade, Cristina Montagna, Yuri Lazebnik, Michael J. Difilippantonio, Jens K. Habermann, Gert Auer, Eytan Ruppin, Thomas Ried
Journal: Genome Medicine (2021)

Abstract Background Many carcinomas have recurrent chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is not completely understood. Methods In this study, we looked at the frequency of chromosomal arm gains and losses in different cancer types from the The Cancer Genome Atlas (TCGA) and compared them to the mean gene expression of each chromosome arm in corresponding normal tissues of origin from the Genotype-Tissue Expression (GTEx) database, in addition to the distribution of tissue-specific oncogenes and tumor suppressors on different chromosome arms. Results This analysis revealed a complex picture of factors driving tumor karyotype evolution in which some recurrent chromosomal copy number reflect the chromosome arm-wide gene expression levels of the their normal tissue of tumor origin. Conclusions We conclude that the cancer type-specific distribution of chromosomal arm gains and losses is potentially “hardwiring” gene expression levels characteristic of the normal tissue of tumor origin, in addition to broadly modulating the expression of tissue-specific tumor driver genes.
Repeat bronchoalveolar lavage in idiopathic pulmonary fibrosis: proceed with caution?
Authors: Mark G. Jones, Martin Kolb
Journal: European Respiratory Journal (2021)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease with a median life expectancy of 3–5 years [1]. In recent years, management of IPF has been transformed with the worldwide approval of two anti-fibrotic therapies. In parallel, advances in the understanding of IPF pathogenesis have identified numerous targets for potential therapeutic intervention [2]. However, the adoption of anti-fibrotic therapies as the standard of care for patients with IPF has further increased the complexity of investigating novel therapeutics in clinical trials. New, innovative clinical trial design approaches are therefore being implemented. This includes early-phase trials designed not only to inform about drug dosing, safety and tolerability, but also to provide sufficient confidence on target engagement or potential efficacy to support progression to the much more costly later-phase studies. Careful deliberation is required when considering repeat bronchoalveolar lavage in patients with idiopathic pulmonary fibrosis <https://bit.ly/3bMyRfZ>