tbuckley/cabot-search huggingface dataset:
Large Extracellular Vesicle-Associated Rap1 Accumulates in Atherosclerotic Plaques, Correlates With Vascular Risks and Is Involved in Atherosclerosis
Authors: Liliana Perdomo, Xavier Vidal-Gómez, Raffaella Soleti, Luisa Vergori, Lucie Duluc, Maggy Chwastyniak, Malik Bisserier, Soazig Le Lay, Alexandre Villard, Gilles Simard, Olivier Meilhac, Frank Lezoualc’h, Ilya Khantalin, Reuben Veerapen, Séverine Dubois, Jérôme Boursier, Samir Henni, Frédéric Gagnadoux, Florence Pinet, Ramaroson Andriantsitohaina, M. Carmen Martínez
Journal: Circulation Research (2020)

Rationale: Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular diseases and atherosclerosis. Circulating levels of large extracellular vesicles (lEVs), submicrometer-sized vesicles released from plasma membrane, from MetS patients were shown to induce endothelial dysfunction, but their role in early stage of atherosclerosis and on vascular smooth muscle cells (SMC) remain to be fully elucidated. Objective: To determine the mechanisms by which lEVs lead to the progression of atherosclerosis in the setting of MetS. Methods and Results: Proteomic analysis revealed that the small GTPase, Rap1 was overexpressed in lEVs from MetS patients compared with those from non-MetS subjects. Rap1 was in GTP-associated active state in both types of lEVs, and Rap1-lEVs levels correlated with increased cardiovascular risks, including stenosis. MetS-lEVs, but not non-MetS-lEVs, increased Rap1-dependent endothelial cell permeability. MetS-lEVs significantly promoted migration and proliferation of human aortic SMC and increased expression of proinflammatory molecules and activation of ERK (extracellular signal-regulated kinase) 5/p38 pathways. Neutralization of Rap1 by specific antibody or pharmacological inhibition of Rap1 completely prevented the effects of lEVs from MetS patients. High-fat diet-fed ApoE −/− mice displayed an increased expression of Rap1 both in aortas and circulating lEVs. lEVs accumulated in plaque atherosclerotic lesions depending on the progression of atherosclerosis. lEVs from high-fat diet-fed ApoE −/− mice, but not those from mice fed with a standard diet, enhanced SMC proliferation. Human atherosclerotic lesions were enriched in lEVs expressing Rap1. Conclusions: These data demonstrate that Rap1 carried by MetS-lEVs participates in the enhanced SMC proliferation, migration, proinflammatory profile, and activation of ERK5/p38 pathways leading to vascular inflammation and remodeling, and atherosclerosis. These results highlight that Rap1 carried by MetS-lEVs may be a novel determinant of diagnostic value for cardiometabolic risk factors and suggest Rap1 as a promising therapeutic target against the development of atherosclerosis. Graphical Abstract: A graphical abstract is available for this article.
AB0315 RETENTION RATE OF ABATACEPT MONOTHERAPY IN AN ITALIAN MULTICENTRIC RHEUMATOID ARTHRITIS COHORT
Authors: D. Iacono, I. Pantano, D. Birra, G. Scalise, M. A. Coscia, V. Messiniti, G. Loi, A. Merchionda, P. Moscato, F. Ciccia
Journal: Annals of the Rheumatic Diseases (2020)

Background: EULAR recommendations focus the importance of Methotrexate (MTX) therapy as a key element in the treatment of patients with Rheumatoid Arthritis (RA), alone as first line therapy and in combination with biological Disease Modifying Anti-rheumatic Drug (bDMARDs). Abatacept (CTLA4-Ig) in Europe is approved for the treatment of moderate to severe active RA in combination with MTX. Several patients, however, discontinue MTX for intolerance, side effects or contraindications, and real-life data demonstrate how, even in patients receiving therapy with MTX, compliance could be suboptimal. The only data on the use of abatacept in monotherapy come from the ORA-Registry, where a worse performance is observed in monotherapy patients. Objectives: To evaluate a multicenter cohort of RA patients treated with Abatacept in patients underwent combined MTX therapy vs monotherapy. Methods: We retrospectively evaluated RA patients, referring to 2 Italian rheumatology centers, treated with Abatacept monotherapy or in combination with MTX. We compared both persistence in therapy and the rate of remission/low disease activity according to Clinical Disease Activity Index (CDAI) between the 2 groups. Results: We enrolled 147 patients, out of them 66 patients were on monotherapy with Abatacept due to intolerance or controindications and 81 in therapy with Abatacept plus MTX. The two cohorts appeared homogeneous in age, gender, disease duration and baseline activity indexes, with the only difference being higher baseline Physician Global assessment (PhGA) values in monotherapy patients. During the follow-up (median duration 24±14 months), the retention rate of Abatacept treatment was 71.2% in MTX patients (median duration 27–15.6 months) and 62.1% in monotherapy patients (median duration 25.2–17.5; p=ns). No differences between the two groups in terms of retention rate, low-disease activity and CDAI remission (log rank p=ns), Breslow p=ns) were detected. Conclusion: In patients with RA with intolerance or contraindication to MTX use, Abatacept monotherapy could be an efficient and safe option even in the long term follow-up. References: [1]Abatacept monotherapy compared with abatacept plus disease-modifying anti-rheumatic drugs in rheumatoid arthritis patients: data from the ORA registry. Truchetet ME et al. Arthritis Res Ther. 2016 Mar 30;18:72. Disclosure of Interests: DANIELA IACONO Speakers bureau: PFIZER, BRISTOL MAYERS SQUIBB, SANOFI, Ilenia Pantano: None declared, domenico birra: None declared, GIUSEPPE SCALISE: None declared, Melania Alessia Coscia: None declared, VALENTINA MESSINITI: None declared, Gabriella Loi: None declared, Anna Merchionda: None declared, Paolo Moscato: None declared, francesco ciccia Grant/research support from: pfizer, novartis, roche, Consultant of: pfizer, novartis, lilly, abbvie, Speakers bureau: pfizer, novartis, lilly, abbvie
GP who accepted £189 000 in gifts from former patient is allowed back on medical register
Authors: Clare Dyer
Journal: BMJ (2020)

A GP who has been suspended from the UK medical register for the past 18 months for accepting £189 000 (€211 000; $238 000) in gifts from an elderly former patient has now been reinstated after settling financial claims from the patient’s family.

Andrea McFarlane’s initial 12 month suspension was extended by six months in January after her former patient’s nephew told a medical practitioners’ tribunal review hearing that she had not done enough to resolve the matter of the outstanding money.

The elderly woman, named only …
Immune Checkpoint Inhibitors for Cancer Therapy in the COVID-19 Era
Authors: Michele Maio, Omid Hamid, James Larkin, Alessia Covre, Maresa Altomonte, Luana Calabrò, Santosh A. Vardhana, Caroline Robert, Ramy Ibrahim, Andrea Anichini, Jedd D. Wolchok, Anna Maria Di Giacomo
Journal: Clinical Cancer Research (2020)

Abstract The potential immune intersection between COVID-19 disease and cancer therapy raises important practical clinical questions and highlights multiple scientific gaps to be filled. Among available therapeutic approaches to be considered, immune checkpoint inhibitors (ICI) seem to require major attention as they may act at the crossroads between cancer treatment and COVID-19 disease, due to their profound immunomodulatory activity. On the basis of available literature evidence, we suggest guidance to consider for treating physicians, and propose areas of clinical and preclinical investigation. Comprehensively, although with the necessary caution, ICI therapy seems to remain a suitable therapeutic option for patients with cancer during the COVID-19 pandemic.
FRI0114 Diagnostic value of nucleosome-specific antibodies in recent active non treated sle
Authors: J Goetz, RL Humbel, JC Monier, J Cohen, C Andre, A Bacquey, A Chevailler, P Chretien, A Escande, C Johannet, F Oskmann, NO Olsson, MF Taillefer, J Sibilia
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The nucleosome is considered as a major antigen in SLE and nucleosome-specific antibodies (Ab) seem to be the most specific and the earliest markers of SLE. <h3>Objectives</h3> To evaluate different methods of detecting anti-nucleosome Abs and determine the diagnostic value of these Abs in recently active SLE. <h3>Methods</h3> A 2 year (1998–99) prospective multicenter study in 13 European Immunopathology Centres (Groupe d'Etude de l'Auto-Immunite). Patients: (i) 55 cases of recently active SLE (evolution &lt; 1 year), (ii) 50 other autoimmune diseases: 31 RA, 15 primary SJÖGREN'S syndrome, 2 scleroderma, 2 unclassified connective tissue disease. IgG anti-nucleosome Abs were detected by ELISA or immunodot using different nucleosome preparations. IgG anti-ds DNA Abs were detected by ELISA (calf thymus and human recombinant plasmid DNA). <h3>Results</h3> 34/55 SLE patients had anti-nucleosome Abs reacting with 4 kits. 16/55 SLE patients had anti-nucleosome Abs reacting with 1 to 3 kits. 5/55 SLE patients were negative for anti-nucleosome Abs. 5/50 patients with other autoimmune diseases had anti-nucleosome Abs. <h3>Conclusion</h3> 50/55 (91%) of patients with recently active SLE had anti-nucleosome Abs (by at least 1 method), 46/55 (84%) also had anti-ds DNA Abs (by ELISA). The sensitivity and the specificity of the anti-nucleosome Abs for SLE depend on the method and the nucleosome preparation.
Abstract 11847: Characterization of Patient Calls at Cardiac Device Clinics: Economic Implications and Opportunities for Improved Efficiency
Authors: Laura Van Heel, Amber Seiler, Theresa Cirocco, Julia Bayer, Laurence M Epstein, Donna Kalenderian, Erin H Gillen, Joel Ayala
Journal: Circulation (2019)

Introduction: The rising number of patients (pts) receiving cardiac implantable electronic devices (CIEDs) with remote monitoring (RM) has increased clinic workload, including time spent interactin...
Quantitative interactome for DIP/Dpr Immunoglubin Superfamily Cell Recognition Proteins
Authors: F. Cosmanescu, P.S. Katsamba, A.P. Sergeeva, G. Ahlsen, S.D. Patel, J.J. Brewer, L. Tan, S. Xu, Q. Xiao, S. Nagarkar-Jaiswal, H. Bellen, S.L. Zipursky, B. Honig, L. Shapiro
Journal: Neuron (2018)
Abstract B40: Trends in lymph node yield for neck dissection and oral cavity carcinoma survival
Authors: Punam Patel, Suraj Kedarisetty, Miriam Lango
Journal: Clinical Cancer Research (2020)

Abstract Objectives: Lymph node yields (LNYs) following neck dissection have been associated with differences in oral cavity cancer survival. The objective of this study was to evaluate temporal trends in LNYs in neck dissections for oral cavity carcinoma. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER 18) database. Inclusion criteria included diagnosis of malignant oral cavity cancer (tongue and floor of mouth) squamous cell carcinomas diagnosed from January 1, 2006-December 31, 2016. Patients with AJCC 6th Edition Stages 1-4a who underwent surgery were included. All-cause age-adjusted mortality for tongue and floor of mouth cancers during this period was assessed using SEER*Stat. Results: The median LNY among 8,580 patients in the sample was 25 LNs (Interquartile range 14-39). LNY statistically increased over time from 22 LNs in 2004 to 27 in 2014 (p &amp;lt; 0.0001). In contrast, there was no change in the median number of positive LNs during the same period (median 2 positive LNs in 2004 and 2014). There was no significant difference in lymph node yield based on sex, region, insurance status, or relative location to a metropolitan center. After adjusting for patient age, sex, race, marital status, regional income, and percent current smokers in the county of residence, tumor subsite and TNM stage, LNY less than 18 was independently associated with a 44% greater risk of death from any cause, compared with greater LNYs (HR 1.44, 95% CI 1.29-1.60, p=.0001). During this period, all-cause age-adjusted mortality declined from 469.7 per 100,000 (468.2-471.2) to 429.0/100,000 (428.2-430.8). Conclusion: LNY following neck dissection for oral tongue and floor of mouth cancers increased significantly over a decade, during which survival also improved. The cause of improved LNY is not known but may nevertheless be contributing to declining mortality in patients with oral tongue and floor of mouth cancers. Citation Format: Punam Patel, Suraj Kedarisetty, Miriam Lango. Trends in lymph node yield for neck dissection and oral cavity carcinoma survival [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B40.
Noninvasive MRI Native T1 Mapping Detects Response to <i>MYCN</i>-targeted Therapies in the Th-<i>MYCN</i> Model of Neuroblastoma
Authors: Konstantinos Zormpas-Petridis, Evon Poon, Matthew Clarke, Neil P. Jerome, Jessica K.R. Boult, Matthew D. Blackledge, Fernando Carceller, Alexander Koers, Giuseppe Barone, Andrew D.J. Pearson, Lucas Moreno, John Anderson, Neil Sebire, Kieran McHugh, Dow-Mu Koh, Louis Chesler, Yinyin Yuan, Simon P. Robinson, Yann Jamin
Journal: Cancer Research (2020)

Abstract Noninvasive early indicators of treatment response are crucial to the successful delivery of precision medicine in children with cancer. Neuroblastoma is a common solid tumor of young children that arises from anomalies in neural crest development. Therapeutic approaches aiming to destabilize MYCN protein, such as small-molecule inhibitors of Aurora A and mTOR, are currently being evaluated in early phase clinical trials in children with high-risk MYCN-driven disease, with limited ability to evaluate conventional pharmacodynamic biomarkers of response. T1 mapping is an MRI scan that measures the proton spin-lattice relaxation time T1. Using a multiparametric MRI-pathologic cross-correlative approach and computational pathology methodologies including a machine learning–based algorithm for the automatic detection and classification of neuroblasts, we show here that T1 mapping is sensitive to the rich histopathologic heterogeneity of neuroblastoma in the Th-MYCN transgenic model. Regions with high native T1 corresponded to regions dense in proliferative undifferentiated neuroblasts, whereas regions characterized by low T1 were rich in apoptotic or differentiating neuroblasts. Reductions in tumor-native T1 represented a sensitive biomarker of response to treatment-induced apoptosis with two MYCN-targeted small-molecule inhibitors, Aurora A kinase inhibitor alisertib (MLN8237) and mTOR inhibitor vistusertib (AZD2014). Overall, we demonstrate the potential of T1 mapping, a scan readily available on most clinical MRI scanners, to assess response to therapy and guide clinical trials for children with neuroblastoma. The study reinforces the potential role of MRI-based functional imaging in delivering precision medicine to children with neuroblastoma. Significance: This study shows that MRI-based functional imaging can detect apoptotic responses to MYCN-targeted small-molecule inhibitors in a genetically engineered murine model of MYCN-driven neuroblastoma.
Protein acetylation derepresses Serotonin Synthesis to potentiate Pancreatic Beta-Cell Function through HDAC1-PKA-Tph1 signaling
Authors: Yuqing Zhang, Shushu Wang, Linlin Zhang, Feiye Zhou, Kecheng Zhu, Qin Zhu, Qianqian Liu, Yun Liu, Lei Jiang, Guang Ning, Yufang Bi, Libin Zhou, Xiao Wang
Journal: Theranostics (2020)

Rationale: Protein acetylation is tightly linked to transcriptional control and energy metabolism. However, the role of protein acetylation in islet function remains enigmatic. This study aims to determine how protein acetylation controls β-cell function and explore the underlying mechanism. Methods: The gene-expression profiles were analyzed for rat islets in response to two histone deacetylase (HDAC) inhibitors. Insulin secretion, tryptophan hydroxylase 1 (Tph1) expression, and serotonin synthesis of rat islets were detected after HDAC inhibitor treatment both in vivo and ex vivo. β-cell-specific Tph1-overexpressing transgenic rats and β-cell-specific Tph1 knockout mice were constructed to evaluate the role of Tph1 in β-cell function. The deacetylation of PKA in β-cells by HDAC1 was investigated by adenoviral infection, immunoprecipitation, and western blot. Results: Inhibition of HDACs greatly potentiated pancreatic β-cell function and reprogrammed transcriptional landscape of islets. Among the commonly up-regulated genes by two pan-HDAC inhibitors, Tph1 displayed the most prominent change. Specifically, inhibition of HDAC1 and HDAC3 by MS-275 strongly promoted Tph1 expression and endogenous serotonin synthesis in rat islets, concomitantly with enhanced insulin secretory capacity in vivo and ex vivo. β-cell-specific Tph1-overexpressing transgenic rats exhibited improved glucose tolerance and amplified glucose-stimulated insulin secretion. On the contrary, β-cell-specific Tph1 knockout mice displayed glucose intolerance and impaired insulin secretion with aging. Moreover, depletion of Tph1 in β-cells abrogated MS-275-induced insulin hypersecretion. Overexpression of HDAC1, not HDAC3, inhibited Tph1 transcriptional activity and decreased MS-275-stimulated Tph1 expression. Mechanistically, HDAC1 deacetylated PKA catalytic subunit and decreased its activity, resulting in Tph1 transcriptional repression. The acetylation mimetic K62Q mutant of PKA increased its catalytic activity. HDAC1 inhibition exerted a synergistic effect with cAMP/PKA signal on Tph1 expression. Conclusions: The present findings highlight a novel role of HDAC1-PKA-Tph1 signaling in governing β-cell functional compensation by derepressing serotonin synthesis.
Reply to Fabiana Gregucci, Roberta Carbonara, and Alba Fiorentino’s Letter to the Editor re: Lisa Moris, Marcus G. Cumberbatch, Thomas Van den Broeck, et al. Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review. Eur Urol 2020;77:614–27
Authors: Lisa Moris, Nicolas Mottet, Thomas Wiegel
Journal: European Urology (2020)
Abstract B09: Inactivating the EGFR-Arf1 axis by HDAC-targeted therapy to suppress invasiveness of head and neck squamous cell carcinoma
Authors: Leilei He, Lixia Gao, Liwei Lang, Chloe Shay, Yong Teng
Journal: Clinical Cancer Research (2020)

Abstract Histone deacetylase (HDAC)-targeted treatment has the great potential to treat head and neck squamous cell carcinoma (HNSCC). However, little has been reported regarding the beneficial role of HDAC inhibition in anti-HNSCC therapy and the underlying molecular mechanisms remain elusive. Here, we demonstrate that ADP-ribosylation factor 1 (Arf1), a small GTPase coordinating vesicle-mediated intracellular trafficking, can be inactivated by HDAC inhibitors TSA and PXD101, through histone acetylation-independent degradation of epidermal growth factor receptor (EGFR) in HNSCC cells. Mechanistically, activated Arf1 (GTP-Arf1) is maintained by binding to phosphorylated EGFR on the cancer cell plasma membrane. Decreased EGFR phosphorylation is associated with reduced EGFR protein levels in the presence of HDAC inhibitors, which inactivates Arf1 and eventually inhibits its dependent invasion in HNSCC cells. This novel finding represents the first example of modulating the EGFR-Arf1 complex in HNSCC by small-molecule agents. Our insights not only explore the critical role of the EGFR-Arf1 complex in driving HNSCC progression, but also shed light onto the molecular events accounting for HDAC-targeted therapy. Citation Format: Leilei He, Lixia Gao, Liwei Lang, Chloe Shay, Yong Teng. Inactivating the EGFR-Arf1 axis by HDAC-targeted therapy to suppress invasiveness of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B09.
THU0553 A HEALTH ECONOMIC ANALYSIS OF THE USE OF COLOUR DOPPLER ULTRASONOGRAPHY AS THE PRIMARY DIAGNOSTIC MODALITY IN PATIENTS WITH SUSPECTED GIANT CELL ARTERITIS
Authors: C. Mukhtyar, L. Steel, C. Jones, M. Bachmann
Journal: Annals of the Rheumatic Diseases (2020)

Background: EULAR has recommended ultrasonography (US) as first imaging modality for diagnosis of Giant Cell Arteritis (GCA) 1 . For patients with a high pre-test probability who have a negative scan, the recommendation is to use another diagnostic modality like temporal artery biopsy (TAB) to make a diagnosis 1 . We know that a fast-track pathway incorporating US, results in better clinical outcomes 2 ; but there are little data on the health-economics of this approach. Since 2017, we have used ultrasonography as the primary diagnostic modality for suspected GCA. In patients with a high pre-test probability with a negative ultrasonography, we perform a temporal artery biopsy. Objectives: To compare the cost of investigating GCA using first-line US and second-line TAB the use of TAB only. To compare the cost per definite diagnosis of GCA. Methods: Number of cases from 2007-2009 and 2017-2019 were calculated by the number of TAB performed and number of referrals to hospital GCA clinic, respectively. Costs of the procedure were calculated as per the nationally agreed tariff by the United Kingdom National Health Service. For ease of comparison, we used the 2018/19 tariff (£1284/TAB; £51 for US) Results: In 2007-2009, 162 cases were referred to clinic and had a TAB, of which 86 were positive. No cases had US. The 2018/19 corrected cost was £208008; the cost per positive diagnosis was £2418.70 (Table 1). In 2017-2019, 419 patients were referred to the GCA clinic, 416 of whom had US for diagnosis. 3 individuals had a TAB as the first diagnostic modality and 66 others were referred for a TAB because of a high pre-test probability and negative US. The 2018/19 corrected cost of this pathway was £109812 and the cost per positive diagnosis was £773.32 (Table 1). Table 1. Numbers of cases investigated for suspected GCA by TAB or US and the costs corrected to 2018/19 UK NHS tariff. Years No of referrals No of TAB No of US No of patients with GCA Total cost Cost of making 1 positive diagnosis 2007-09 162 162 0 86 £208008 £2418.70 2017-19 419 69 416 142 £109812 £773.32 If all cases in 2017-2019 had a TAB for suspected GCA, the 2018/19 corrected cost would have been £537996. The estimated 2018/19 corrected savings in our center was £142728/year. The estimated 2018/19 corrected savings per definite diagnosis of GCA has dropped by £1645.37 (Table 1). Conclusion: The EULAR recommendation of using first-line US for diagnosis of GCA followed by a TAB in cases with uncertain diagnosis after US, is highly cost-effective in the UK, resulting in cost savings of &gt;£140K per year. References: [1]Dejaco C, et al. Ann Rheum Dis. 2018 May;77(5):636-643. [2]Diamantopoulos AP, et al. Rheumatology (Oxford). 2016 Jan;55(1):66-70. Disclosure of Interests: None declared
Extended ncRNAs Interfere with Promoter Nucleosome Dynamics
Authors: Tomasz W. Turowski, David Tollervey
Journal: Trends in Genetics (2020)

Eukaryotic genomes generate vast numbers of non-protein-coding RNAs (ncRNAs) that can inhibit mRNA synthesis through transcription interference, but the mechanisms are unclear. Gill et al. show that transcription of antisense ncRNAs induces 'elongation marks' on histones in promoter regions. These inhibit active nucleosome positioning required to maintain open transcription-initiation sites.